MODIFICATION TO DIMENSION NT-PROBNP FLEX REAGENT CARTRIDGE METHOD

K042347 · Dade Behring, Inc. · NBC · Nov 19, 2004 · Clinical Chemistry

Device Facts

• Record ID: K042347
• Device Name: MODIFICATION TO DIMENSION NT-PROBNP FLEX REAGENT CARTRIDGE METHOD
• Applicant: Dade Behring, Inc.
• Product Code: NBC · Clinical Chemistry
• Decision Date: Nov 19, 2004
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Intended Use

The PBNP assay used on the Dimension® clinical chemistry system with the heterogeneous immunoassay module is an in vitro diagnostic assay for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human plasma. In individuals suspected of having congestive heart failure (CHF), measurements of NT-proBNP are used as an aid in the diagnosis and assessment of severity. The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure.

Device Story

In vitro diagnostic assay; quantitative determination of NT-proBNP in human plasma; used on Dimension clinical chemistry systems. Principle: one-step sandwich enzyme immunoassay; sample incubated with chromium dioxide particles coated with polyclonal antibodies; conjugate reagent (alkaline phosphatase-labeled polyclonal antibody) added; magnetic separation/washing removes unbound conjugate; sandwich-bound ALP triggers amplification cascade; produces colored product absorbing at 510 nm; color intensity proportional to NT-proBNP concentration. Used in clinical laboratories; operated by trained personnel. Output: numerical concentration value (pg/mL). Clinical utility: aids diagnosis of CHF; assesses disease severity (NYHA classes); risk stratifies acute coronary syndrome and heart failure patients. Benefits: provides objective biomarker data to support clinical decision-making regarding heart failure management.

Clinical Evidence

Clinical study evaluated 308 individuals without CHF and 227 patients with CHF. Primary endpoints: clinical sensitivity and specificity using age-stratified cut-offs (125 pg/mL for <75 yrs; 450 pg/mL for ≥75 yrs). Results: AUC 0.921 (95% CI 0.898-0.943). Sensitivity ranged 77-92%; specificity 77-97% across age/gender subgroups. Data demonstrated relationship between NT-proBNP levels and NYHA functional classes (I-IV), supporting use for severity assessment.

Technological Characteristics

One-step sandwich enzyme immunoassay; chromium dioxide particles; alkaline phosphatase (ALP) conjugate; synthetic flavin adenine dinucleotide phosphate (FADP) amplification; 510 nm absorbance measurement. Compatible with Dade Behring Dimension RxL Max, RxL, and Xpand systems. Sample types: lithium heparin, sodium heparin, EDTA plasma. Standards: NCCLS EP 5-A.

Indications for Use

Indicated for quantitative determination of NT-proBNP in human plasma to aid in diagnosis of suspected congestive heart failure and for risk stratification and severity assessment in patients with acute coronary syndrome and 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

• Roche Diagnostics Elecsys® proBNP immunoassay (K022516/K032646)

Submission Summary (Full Text)

{0}------------------------------------------------

# NOV 1 9 2004

### SUMMARY OF SAFETY AND EFFECTIVENESS INFORMATION

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.

| Submitter's Name: | George M. Plummer<br>Dade Behring Inc.<br>P.O. Box 6101<br>Newark, DE 19714-6101 |
|-----------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Date of Preparation: | August 27, 2004 |
| Name of Product(s): | Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method |
| FDA Classification Name(s): | B-type natriuretic peptide test system (Class II) |
| FDA Guidance Documents: | "Class II Special Control Guidance Document for B-Type Natriuretic<br>Peptide Premarket Notifications; Final Guidance for Industry and<br>FDA Reviewers" - 11/30/2000 |
| Predicate Device(s): | Roche Diagnostics Elecsys® proBNP immunoassay<br>(K022516/K032646) |

# Device Description(s):

#### Method

The Dade Behring Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method is an in vitro diagnostic test that consists of prepackaged reagents in a flexible plastic cartridge for use only on the Dimension® clinical chemistry system. The PBNP method is a one step enzyme immunoassay based on the "sandwich" principle. Sample is incubated with chromium dioxide particles coated with polyclonal antibodies which recognize epitopes located in the N-terminal part of proBNP, and a conjugate reagent [alkaline phosphatase (ALP)] labeled polyclonal antibody specific for a second independent epitope on NT-proBNP, to form a particle/NT-proBNP/conjugate sandwich. Unbound conjugate is removed by magnetic separation and washing. After separation and washing, the particle/NT-proBNP/conjugate sandwich is transferred to the cuvette where the sandwich-bound ALP triggers an amplification cascade * ALP dephosphorylates synthetic flavin adenine dinucleotide phosphate (FADP) to produce FAD. FAD binds to apo D-amino acid oxidase and converts it to active holo D-amino acid oxidase. Each molecule of holo D-amino acid oxidase produces multiple molecules of hydrogen peroxide (H2O2). H2O2 in the presence of horseradish peroxidase (HRP), converts 3,5-dichloro-2-hydroxybenzenesulfonic acid (DCHBS) and 4-aminoantipyrine (4-AAP) to a colored product that absorbs at 510 nm. The color change measured is directly proportional to the concentration of proBNP present in the patient sample.

*Technology licensed from London Biotechnology, Ltd., London, U.K.

{1}------------------------------------------------

# Intended Use:

## Method

The Dimension® PBNP Flex® method is an in vitro diagnostic assay for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human plasma. Measurements of NT-proBNP are used as an aid in the diagnosis and assessment of severity of individuals suspected of having congestive heart failure and for risk stratification of patients with acute coronary syndrome and heart failure.

# Comparison to Predicate Device:

### Method

A summary of the features of the Dade Behring Dimension® PBNP Flex® method and the predicate Roche Diagnostics Elecsys® proBNP immunoassay is provided in the following chart. The Dade Behring Dimension® PBNP Flex® method utilizes the Roche polyclonal (sheep) antibody/antigen set.

| Feature | Dimension® PBNP<br>(K041417) | Roche Elecsys® proBNP<br>(K032646/K022516) |
|---------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | For the in vitro quantitative<br>determination of N-terminal<br>pro-brain natriuretic peptide in<br>human plasma as an aid in the<br>diagnosis and assessment of<br>severity of individuals suspected of<br>having congestive heart failure.<br>The test is further indicated for the<br>risk stratification of patients with<br>acute coronary syndrome and heart<br>failure. | For the in vitro quantitative<br>determination of N-terminal<br>pro-<br>brain natriuretic peptide in human<br>serum and plasma as an aid in the<br>diagnosis of individuals suspected of<br>having congestive heart failure.<br>The test is further indicated for the<br>risk stratification of patients with<br>acute coronary syndrome and<br>congestive heart failure. |
| Assay Type<br>(detection) | immunoassay<br>(photometric) | immunoassay<br>(electrochemiluminescent) |
| Reportable Range | 5 - 30,000 pg/mL | 5 - 35,000 pg/mL |
| Antibody | Roche Diagnostics'<br>polyclonal (sheep) antibody | polyclonal (sheep) antibody |
| Cut-off | 125 pg/mL for patients less than 75<br>years and 450 pg/mL for patients 75<br>years and older | 125 pg/mL for patients less than 75<br>years and 450 pg/mL for patients 75<br>years and older |
| Feature | Dimension® PBNP<br>(K041417) | Roche Elecsys® proBNP<br>(K032646/K022516) |
| Analytical<br>Sensitivity | ≤ 10 pg/mL | 5 pg/mL |
| Functional<br>Sensitivity | ≤ 30 pg/mL | < 50 pg/mL |
| Analytical<br>Specificity | Natercor® shows no significant<br>cross reactivity,0 or 125 pg/mL NT-<br>proBNP; sixteen other substances<br>show no significant cross reactivity | Natercor® shows no significant cross<br>reactivity, 300 pg/mL or 3000 pg/mL<br>NT-proBNP; sixteen other substances<br>show no significant cross reactivity |
| Interferences | No significant interference from:<br>bilirubin ,conj. up to 60 mg/dL<br>bilirubin, unconj. up to 20 mg/dL<br>hemoglobin up to 1000 mg/dL<br>triglycerides up to 3000 mg/dL<br>rheumatoid factors up to 500 IU/mL | No significant interference from:<br>bilirubin up to 35 mg/dL<br>hemoglobin up to 1.4 g/dL<br>triglycerides up to 4000 mg/dL<br>rheumatoid factors up to 1500 IU/mL |
| Reference | Roche NT-proBNP antibody (1-76) | Roche NT-proBNP antibody (1-76) |
| Hook Effect | No effect up to 300,000 pg/mL | No effect up to 300,000 pg/mL |
| Calibration Interval | 30 days - same reagent lot | 30 days - same reagent lot |
| Sample Volume | 50 uL | 20 uL |
| Reproducibility | Within Run<br>2.2 % CV @ 159 ng/mL<br>1.8% CV @ 484.3<br>1.6% @ 1037.8 ng/mL<br>1.2% CV @ 184.7 ng/mL<br>1.9% CV @ 4062.4 ng/mL<br>Total<br>5.7 % CV @ 159 ng/mL<br>3.7% CV @ 484.3<br>3.7% @ 1037.8 ng/mL<br>4.0% CV @ 184.7 ng/mL<br>3.1% CV @ 4062.4 ng/mL | Within Run<br>2.7% CV @ 175 ng/mL<br>2.4% CV @ 355 ng/mL<br>1.8% CV @ 434 ng/mL<br>1.9% CV @ 1068 ng/mL<br>1.8% CV @ 4962 ng/mL<br>1.8% CV @ 6781 ng/mL<br>Total<br>3.2% CV @ 175 ng/mL<br>2.9% CV @ 355 ng/mL<br>2.6% CV @ 434 ng/mL<br>2.3% CV @ 1068 ng/mL<br>2.4% CV @ 4962 ng/mL<br>2.2% CV @ 6781 ng/mL |

{2}------------------------------------------------

{3}------------------------------------------------

#### Comments on Substantial Equivalence:

Both the Dade Behring Dimension® PBNP and the Roche Elecsys® proBNP immunoassays are intended for the quantitative determination of NT-proBNP. Comparative data for human plasma samples demonstrate good analytical and clinical agreement between the methods.

#### Conclusion:

The Dade Behring Dimension® PBNP Flex® method and the predicate Roche Elecsys® proBNP immunoassay (K032646) are substantially equivalent based on their intended use and performance characteristics as described above.

> George M. Plummer Regulatory Affairs and Compliance Manager August 27, 2004

{4}------------------------------------------------

DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" around the perimeter. Inside the circle is an abstract image of an eagle with its wings spread.

NOV 1 9 2004

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Mr. George Plummer Regulatory Affairs and Compliance Manager Dade Behring, Inc. P.O. Box 6101 Newark, DE 19714

Re: k042347

> Trade/Device Name: Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method Regulation Number: 21 CFR 862.1117 Regulation Name: B-type natriuretic peptide test system Regulatory Class: Class II Product Code: NBC Dated: November 2, 2004 Received: November 3, 2004

Dear Mr. Plummer:

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).

{5}------------------------------------------------

# 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,

Sincerely yours,

Cornelia B. Parks

Cornelia B. Rooks. MA Acting Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

{6}------------------------------------------------

# Indications For Use Statement

510(k) Number (if known): K042347

#### Device Name:

Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method

#### Indications for Use:

The Dimension® PBNP Flex® method is an in vitro diagnostic assay for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human plasma. Measurements of NT-proBNP are used as an aid in the diagnosis of individuals suspected of having congestive heart failure and for risk stratification and severity assessment of patients with acute coronary syndrome and heart failure.

| Prescription Use | <div> <span></span> </div> |
|-----------------------------|----------------------------|
| (Part 21 CFR 801 Subpart D) | |

AND/OR

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

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Carol Beman
Division Sign-Off

Office of in Vitro Diagnostic Device Evaluation and Safety

510(k) K042347

Page 1 of