ADVIA IMMUNO MODULAR SYSTEM (IMS) B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAY

K051265 · Bayer Healthcare, LLC · NBC · Jun 13, 2005 · Clinical Chemistry

Device Facts

• Record ID: K051265
• Device Name: ADVIA IMMUNO MODULAR SYSTEM (IMS) B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAY
• Applicant: Bayer Healthcare, LLC
• Product Code: NBC · Clinical Chemistry
• Decision Date: Jun 13, 2005
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Intended Use

The Bayer ADVIA IMS BNP method is for in vitro diagnostic use in the quantitative determination of B-type Natriuretic Peptide (BNP) in human plasma using the ADVIA IMS® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of the severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. This assay is not intended for use on any other system.

Device Story

The ADVIA IMS BNP Assay is an in vitro heterogeneous sandwich immunoassay for human EDTA plasma. It utilizes two monoclonal antibodies: one labeled with FITC and another conjugated to alkaline phosphatase (ALP). The assay uses magnetic separation to capture the sandwich complex. A dioxetane phosphate derivative substrate is dephosphorylated by ALP, producing photon emission measured by a photomultiplier tube. The device is used in clinical laboratory settings by trained personnel. The output is a quantitative BNP concentration (10 to 6,000 pg/mL). Healthcare providers use these results to aid in the diagnosis and severity assessment of heart failure and to predict survival and future heart failure risk in patients with acute coronary syndromes.

Clinical Evidence

Clinical evidence includes retrospective studies on 438 MI patients and 2525 ACS patients. BNP levels >80 pg/mL correlated with increased 30-day mortality (OR 11.5) and composite endpoints of death/heart failure. Sensitivity/specificity data derived from predicate (ADVIA Centaur) studies across age/gender groups; 100 pg/mL threshold provides >97% specificity for heart failure diagnosis. Analytical performance: precision (total CV 1.8-4.1%), linearity (84-109% recovery), and MDC (~4 pg/mL).

Technological Characteristics

Heterogeneous sandwich immunoassay; magnetic separation; monoclonal antibodies; alkaline phosphatase (ALP) enzyme conjugate; dioxetane phosphate substrate; photomultiplier tube detection; liquid reagents; 2-8 °C storage; multi-point calibration.

Indications for Use

Indicated for quantitative measurement of plasma BNP in patients to aid in diagnosis and severity assessment of heart failure. In patients with acute coronary syndromes (ACS), used with other risk factors to predict survival and likelihood of future heart failure. For use on ADVIA IMS System 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

• ADVIA Centaur® BNP assay (k031038)
• ACS:180 BNP assay (k040425, k043228)

Submission Summary (Full Text)

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# JUN 1 3 2005

## 510(k) SUMMARY OF SAFETY AND EFFECTIVENESS BNP Assay for Bayer ADVIA® Integrated Modular System (IMS)

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

The assigned 510(k) number is: k051265

### June 6, 2005

## 1. Submitter's name, address and telephone number:

Andres Holle Manager, Regulatory Affairs Bayer HealthCare LLC A subsidiary of Bayer Corporation 511 Benedict Avenue Tarrytown, NY 10591 TEL: [phone] FAX: [phone] Email: andres holle [e-mail]

### 2. Name of the device:

| a) | Classification Names: B-type natriuretic peptide test systems, §862.1117 |
|-----------------|--------------------------------------------------------------------------|
| Classification: | Class II |
| Product Code: | NBC |

- b) Common name: BNP assays
- c) Proprietary name: ADVIA Immuno Modular System (IMS)® B-Type Natriuretic Peptide (BNP) Assay

### d) The device:

| Product Name | Reagent Part<br># / BAN Number | Calibrator Part<br># / BAN Number |
|---------------------|--------------------------------|-----------------------------------|
| ADVIA IMS BNP Assay | 0154537<br>(100 tests) | 00155177 |

### 3. Predicate Device:

| Product Name | Reagent Part # | Master Curve<br>Material Part # |
|-------------------------|------------------------------------------------------------|---------------------------------|
| ADVIA Centaur BNP Assay | REF 02816634<br>(500 tests)<br>REF 02816138<br>(100 tests) | REF 02815905 |

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## 4. Description of the device:

The ADVIA IMS BNP Assay is an in vitro immunoassay intended for the quantitative measurement of b-type natriuretic peptide (BNP) in human EDTA plasma covering the analytical range of 10 to approximately 6,000 pg/mL. The assay is a heterogeneous sandwich immunoassay using magnetic separation. Reagony a a freel genedus monoclonal antibody to BNP labeled with FITC and Reagent 2 (R2) contains the second monoclonal antibody to BNP (F(ab)2) conjugated to the enzyme /kaline phosphatase (ALP). The monoclonal antibodies used in the ADVIA IMS BNP assay are identical to those used in the ADVIA Centaur assay. The sandwich complex formed by the modite and the antibody conjugates is captured by the magnetic particles so that the BNP concentration in the sample can be measured in terms of enzyme activity. The substrate used for this assay is a dioxetane phosphate derivative, which is dephosphorylated by ALP resulting in photon emission. Luminescence is measured by a photomultiplier tube. The dose response curve is proportional to the analyte concentration in sample

The Centaur BNP Master Curve Material (MCM) (part number 02815905) will be used as the calibrators (six levels) for the ADVIA IMS BNP assay. The controls used in the ADVIA IMS BNP assay, QC BNP 1, 2, 3 (REF 02817045), are existing Bayer Centair products consisting of three levels of lyophilized controls. The controls contain various concentrations of BNP in buffered sodium caseinate with preservative.

### 5. Intended Use

For in vitro diagnostic use in the quantitative determination of B-type Natriuretic Peptide (BNP) in human plasma using the ADVIA IMS® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of the severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. This assay is not intended for use on any other system.

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| | ADVIA IMS BNP assay | ADVIA Centaur BNP assay<br>(predicate device) |
|---------------------------------|------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|
| Intended Use | Same | Same |
| Summary | Same | Same |
| Principle | Heterogeneous Sandwich<br>Magnetic Separation Assay | Heterogeneous Sandwich<br>Magnetic Separation Assay |
| Reagents | Two liquid reagents contained<br>in system specific packaging | Two liquid reagents contained<br>in system specific packaging |
| Storage | 2-8 °C | 2-8 °C |
| Stability | Same | Same |
| Precautions | Same | Similar |
| Indications of<br>Deterioration | Same | Same |
| Performance<br>Characteristics | Same | Same |
| Limitations | Same | Same |
| Parameters | Multi-point calibration,<br>sandwich immunoassay and<br>system specific parameters | Multi-point calibration,<br>sandwich immunoassay and<br>system specific parameters |

## 6. Similarities and Differences between ADVIA® IMS™ BNP assay and Bayer Centaur® BNP assay:

7.

#### 7. Performance summary:

#### a) Imprecision:

| | ADVIA IMS | ADVIA Centaur | | |
|--------------------------------------|-----------|------------------|----------------|--|
| Level<br>Total<br>(pg/mL) <br>CV(%) | | Level<br>(pg/mL) | Total<br>CV(%) | |
| 71 | 4.1 | 48.5 | 3.5 | |
| 716 | 1.9 | 458 | 2.8 | |
| 2660 | 1.8 | 1736 | 2.9 | |

## b) Correlation:

| Specimen type | Comparison<br>System (X) | N | Regression<br>Equation | Syx<br>(pg/mL) | R | Sample<br>Range<br>(pg/mL) |
|---------------|--------------------------|-----|------------------------|----------------|-------|----------------------------|
| EDTA Plasma | ADVIA<br>Centaur | 360 | $0.990 * X + 4.37$ | 111.7 | 0.992 | 4 to 4531 |

(Y= ADVIA IMS, X= comparison system)

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### c) Interfering substances:

| Interference | Interference Conc.<br>mg/dL | Recovery (pg/mL) | | %<br>Deviation |
|---------------|-----------------------------|------------------|----------|----------------|
| | | Expected | Observed | |
| Albumin | 7,000 | 145.3 | 131.5 | -9.46 |
| | | 407.5 | 377.9 | -7.27 |
| Bilirubin | 25 | 79.4 | 80.6 | 1.50 |
| | | 366.1 | 356.4 | -2.65 |
| Cholesterol | 1,000 | 133.8 | 139.5 | 4.26 |
| | | 352.8 | 383.6 | 8.73 |
| Creatinine | 2.5 | 99.2 | 100.0 | 0.76 |
| | | 427.0 | 419.0 | -1.87 |
| Hemoglobin | 750 | 86.7 | 78.3 | -9.68 |
| | | 402.3 | 366.7 | -8.86 |
| Triglyceride | 800 | 86.2 | 83.4 | -3.19 |
| | | 389.4 | 384.3 | -1.32 |
| Urea Nitrogen | 200 | 87.7 | 88.9 | 1.34 |
| | | 380.2 | 382.0 | 0.48 |
| IgG | 4,600 | 129.3 | 141.2 | 9.15 |
| | | 398.7 | 435.8 | 9.30 |

### d). Analytical Range:

4 pg/mL (1.1 pmol/L) to calibrator level 6 concentration (about 6000 pg/mL or 1728 pmol/L)

### e) Minimum Detectable Concentration:

| ADVIA IMS BNP (pg/mL) | ADVIA Centaur BNP (pg/mL) |
|-----------------------|---------------------------|
| 4 | 2 |

### f) Expected Results:

.

The expected values were determined from clinical studies performed for the predicate ADVIA Centaur BNP Test and results of the studies are included in the labeling for the ADVIA IMS BNP assay.

BNP concentrations in the Reference Group are shown in the tables below. The decision threshold was determined by the 95% confidence limit of BNP in the Reference population. The most appropriate decision threshold apparent from these distributions is 100 pg/mL. This BNP value translates into a general specificity of the test of greater than 97 %.

### Reference Group

To establish the expected results, the circulating BNP concentration was determined from 1521 individuals without heart failure (785 women and 736 men). This population included apparently healthy individuals and individuals with hypertension, diabetes, renal insufficiency, and chronic obstructive pulmonary disease. The

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descriptive statistics for BNP concentrations in the population without heart failure are shown in the following tables. These values are representative of the results obtained from clinical studies.

| All | Age Group | | | | | |
|------------------------|-----------|-----------|-------------|-------------|-------------|------------|
| | All | <45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years |
| Mean, pg/mL | 23.2 | 11.9 | 15.6 | 19.5 | 28.3 | 60.3 |
| SD, pg/mL | 32.5 | 12.9 | 15.9 | 22.6 | 25.4 | 73.0 |
| Median, pg/mL | 14.5 | 8.6 | 10.4 | 13.8 | 22.1 | 43.7 |
| 95th Percentile, pg/mL | 70.8 | 33.3 | 46.7 | 53.2 | 72.3 | 176 |
| % < 100 pg/mL | 97.4 | 99.7 | 99.7 | 98.8 | 97.0 | 85.5 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | <2 | <2 |
| Maximum, pg/mL | 576 | 128 | 119 | 286 | 164 | 576 |
| N | 1521 | 317 | 291 | 403 | 365 | 145 |

| Males | Age Group | | | | | | |
|------------------------|-----------|--------------|----------------|----------------|----------------|---------------|--|
| | All | <45<br>years | 45-54<br>years | 55-64<br>years | 65-74<br>years | 75 +<br>years | |
| Mean, pg/mL | 17.9 | 9.1 | 11.2 | 14.5 | 25.8 | 41.9 | |
| SD, pg/mL | 22.9 | 9.4 | 11.8 | 13.9 | 25.1 | 48.8 | |
| Median, pg/mL | 11.3 | 5.9 | 7.6 | 11.9 | 17.8 | 26.1 | |
| 95th Percentile, pg/mL | 54.3 | 29.4 | 32.8 | 38.8 | 67.6 | 121 | |
| % < 100 pg/mL | 98.6 | 100 | 100 | 99.5 | 96.8 | 94.6 | |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | <2 | <2 | |
| Maximum, pg/mL | 250 | 56.6 | 88.9 | 132 | 151 | 250 | |
| N | 736 | 129 | 140 | 223 | 188 | 56 | |
| Females | Age Group | | | | | | |
| | All | <45<br>years | 45-54<br>years | 55-64<br>years | 65-74<br>years | 75 +<br>years | |
| Mean, pg/mL | 28.1 | 13.8 | 19.8 | 25.6 | 31.0 | 71.9 | |
| SD, pg/mL | 38.8 | 14.6 | 18.0 | 29.0 | 25.5 | 82.9 | |
| Median, pg/mL | 18.5 | 10.4 | 14.8 | 19.4 | 25.7 | 54.3 | |
| 95th Percentile, pg/mL | 86.1 | 35.9 | 56.7 | 75.5 | 72.9 | 167 | |
| % < 100 pg/mL | 96.3 | 99.5 | 99.3 | 97.8 | 97.1 | 79.8 | |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | <2 | <2 | |
| Maximum, pg/mL | 576 | 128 | 119 | 286 | 164 | 576 | |
| N | 785 | 188 | 151 | 180 | 177 | 89 | |

### Patients with Heart Failure

To establish the expected results for the ADVIA Centaur BNP assay in individuals with heart failure, plasma samples were obtained from 722 patients diagnosed with heart failure (264 women and 458 men). The descriptive statistics

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for BNP concentrations in patients with heart failure are presented in the following tables. These values are representative of the results obtained from clinical studies. Each laboratory should establish a reference range representing the patient population being evaluated. In addition, laboratories should be aware of the propertive institution's current practice for the evaluation of heart failure.

| | NYHA Functional Class | | | | |
|------------------------|-----------------------|--------|---------|----------|---------|
| | All | NYHA I | NYHA II | NYHA III | NYHA IV |
| Mean, pg/mL | 505 | 178 | 270 | 525 | 1134 |
| SD, pg/mL | 711 | 347 | 402 | 576 | 1141 |
| Median, pg/mL | 262 | 64.3 | 130 | 355 | 843 |
| 5th percentile, pg/mL | 10.8 | 1.6 | 5.4 | 21.1 | 109 |
| 95th percentile, pg/mL | 1873 | 772 | 999 | 1696 | 3157 |
| % > 100 pg/mL | 72.6 | 43.1 | 58.7 | 82.0 | 95.8 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | 4.0 |
| Maximum, pg/mL | 6989 | 2310 | 3107 | 4052 | 6989 |
| N | 722 | 72 | 242 | 289 | 119 |

Heart Failure Population – All

Heart Failure Population – Males

| | NYHA Functional Class | | | | |
|------------------------|-----------------------|--------|---------|----------|---------|
| | All | NYHA I | NYHA II | NYHA III | NYHA IV |
| Mean, pg/mL | 518 | 121 | 308 | 542 | 1214 |
| SD, pg/mL | 726 | 135 | 475 | 588 | 1200 |
| Median, pg/mL | 245 | 77.7 | 135 | 339 | 950 |
| 5th percentile, pg/mL | 10.7 | 3.9 | 4.4 | 23.2 | 71.5 |
| 95th percentile, pg/mL | 1946 | 400 | 1280 | 1852 | 3157 |
| % > 100 pg/mL | 72.9 | 44.7 | 61.3 | 81.4 | 93.9 |
| Minimum, pg/mL | <2 | <2 | <2 | <2 | 33.7 |
| Maximum, pg/mL | 6989 | 552 | 3107 | 3503 | 6989 |
| N | 458 | 47 | 150 | 194 | 66 |

Heart Failure Population - Females

| | NYHA Functional Class | | | | |
|------------------------|-----------------------|--------|---------|----------|---------|
| | All | NYHA I | NYHA II | NYHA III | NYHA IV |
| Mean, pg/mL | 482 | 285 | 207 | 492 | 1034 |
| SD, pg/mL | 687 | 551 | 228 | 556 | 1068 |
| Median, pg/mL | 291 | 62.5 | 117 | 355 | 779 |
| 5th percentile, pg/mL | 11.0 | 0 | 9.5 | 15.9 | 115 |
| 95th percentile, pg/mL | 1575 | 1447 | 552 | 1518 | 2970 |
| % > 100 pg/mL | 72.0 | 40.0 | 54.3 | 83.2 | 98.1 |
| Minimum, pg/mL | <2 | <2 | <2 | 4.8 | 4.0 |
| Maximum, pg/mL | 5845 | 2310 | 1231 | 4052 | 5845 |
| N | 264 | 25 | 92 | 94 | 53 |

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These results show that there is a relationship between the severity of the clinical signs and symptoms of heart failure and the median BNP concentrations, demonstrating that the assay can be used as an aid in the diagnosis of all degrees of heart failure severity, including asymptomatic patients.

Andres Holle Manager Regulatory Affairs Bayer Corporation 511 Benedict Avenue Tarrytown, New York 10591-5097

.

Date

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Image /page/7/Picture/2 description: The image shows the seal of the Department of Health & Human Services (HHS). The seal features a stylized eagle with its wings spread, symbolizing protection and service. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" are arranged in a circular pattern around the eagle.

JUN 1 3 2005

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Mr. Andres Holle Manger, Regulatory Affairs Bayer HealthCare LLC 511 Benedict Avenue Tarrytown, NY 10591

k051265 Re:

Trade/Device Name: B-type Natriuretic Peptide (BNP) Assay for the ADVIA IMS Regulation Number: 21 CFR 862.1117 Regulation Name: B-type natriuretic peptide test system Regulatory Class: Class II Product Code: NBC Dated: May 12, 2005 Received: May 17, 2005

Dear Mr. Holle:

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 n may of cable 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/industry/support/index.html.

Sincerely yours,

Carol C. Benem

Carol C. Benson, M.A. Acting Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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# Indications for Use

510(k) Number (if known): K051265

Device Name: B-type Natriuretic Peptide (BNP) Assay for the ADVIA IMS

Indications for Use:

The Bayer ADVIA IMS BNP method is for in vitro diagnostic use in the quantitative determination of B-type Natriuretic Peptide (BNP) in human plasma using the ADVIA IMS® System. This assay is indicated for the measurement of plasma BNP as an aid in the diagnosis and assessment of the severity of heart failure. In patients with acute coronary syndromes (ACS), this test, in conjunction with other known risk factors, can also be used to predict survival as well as to predict the likelihood of future heart failure. This assay is not intended for use on any other system.

Prescription Use (Part 21 CFR 801 Subpart D) AND/OR

Over-The-Counter Use (21 CFR 807 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Ruth Chesler

Division Sign-Off

Page 1 of ____________________________________________________________________________________________________________________________________________________________________

Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K051265