DIMENSION NT-PROBNP FLEX REAGENT CARTRIDGE METHOD, DIMENSION PBNP CALIBRATOR, MODELS RF423, RC423

K041417 · Dade Behring, Inc. · NBC · Jul 20, 2004 · Clinical Chemistry

Device Facts

• Record ID: K041417
• Device Name: DIMENSION NT-PROBNP FLEX REAGENT CARTRIDGE METHOD, DIMENSION PBNP CALIBRATOR, MODELS RF423, RC423
• Applicant: Dade Behring, Inc.
• Product Code: NBC · Clinical Chemistry
• Decision Date: Jul 20, 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 heterogenous immunoassay module 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 (CHF). The PBNP Calibrator is an in vitro diagnostic product intended to be used to calibrate the N-terminal pro-brain natriuretic peptide (NT-proBNP) method for the Dimension® clinical chemistry system with the heterogenous immunoassay module.

Device Story

The Dimension® NT-proBNP Flex® reagent cartridge is an in vitro diagnostic assay for use on the Dimension® clinical chemistry system. It utilizes a one-step sandwich enzyme immunoassay principle. Patient plasma samples are incubated with chromium dioxide particles coated with polyclonal antibodies (recognizing the N-terminal part of proBNP) and an alkaline phosphatase (ALP)-labeled polyclonal antibody. After magnetic separation and washing, the sandwich-bound ALP triggers an amplification cascade: ALP dephosphorylates synthetic flavin adenine dinucleotide phosphate (FADP) to FAD; FAD activates apo D-amino acid oxidase; the resulting holo D-amino acid oxidase produces hydrogen peroxide (H2O2). H2O2, in the presence of horseradish peroxidase, converts DCHBS and 4-AAP into a colored product measured at 510 nm. The color intensity is directly proportional to NT-proBNP concentration. The device is operated by laboratory personnel in a clinical setting. Results assist clinicians in diagnosing CHF. The calibrator is a frozen liquid containing synthetic human NT-proBNP in a bovine albumin matrix used to calibrate the assay.

Clinical Evidence

Clinical study evaluated 308 non-CHF individuals and 227 CHF patients. Sensitivity/specificity calculated using age-stratified cut-offs (125 pg/mL <75 yrs; 450 pg/mL ≥75 yrs). Sensitivity ranged 77-91%; specificity 77-94%. ROC analysis yielded AUC 0.916 (95% CI 0.892-0.939).

Technological Characteristics

One-step enzyme immunoassay; sandwich principle. Reagents in flexible plastic cartridge. Chromium dioxide particles; polyclonal sheep antibodies; ALP conjugate; FADP substrate. Colorimetric detection at 510 nm. Requires Dimension clinical chemistry system. Plasma samples (lithium heparin, sodium heparin, EDTA).

Indications for Use

Indicated for the quantitative determination of NT-proBNP in human plasma to aid in the diagnosis of individuals suspected of having congestive heart failure (CHF).

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 and CalSet calibrator (K032646/K022516)

Submission Summary (Full Text)

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K041417

# JUL 2 0 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: | Richard M. Vaught<br>Dade Behring Inc.<br>P.O. Box 6101<br>Newark, DE 19714-6101 |
|-----------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Date of Preparation: | May 26, 2004 |
| Name of Product(s): | Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method,<br>and Dimension® PBNP Calibrator |
| FDA Classification Name(s): | B-type natriuretic peptide test system and calibrator (both 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 and CalSet<br>calibrator (K032646/K022516) |

#### 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 an epitope 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/coniugate 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.

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## Calibrator

Cantorator
The Dade Behring PBNP Calibrator is a frozen liquid product containing synthetic human NT-proBNP in a bovine albumin matrix with stabilizers and preservative. The kit consists of ten vials, two vials at each of five levels, 1.0 mL in each vial.

#### 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 of individuals suspected of having congestive heart failure (CHF).

#### Calibrator

The PBNP Calibrator is an in vitro diagnostic product intended to be used to calibrate the N-terminal probrain natriuretic peptide (PBNP) method for the Dade Behring Dimension® clinical chemistry system with the heterogeneous immunoassay module.

#### Comparison to Predicate Device:

A summary of the features of the Dade Behring Dimension® PBNP Flex® method and the predicate Roche Diagnostics Elecsys® proBNP immunoassay (K032646/K022516) is provided in the following chart. The Dade Behring Dimension® PBNP assay utilizes the same antibody/antigen set as the predicate, Roche Diagnostics Elecsys® proBNP immunoassay.

| Feature | Dimension® PBNP | Roche Elecsys® proBNP |
|---------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | For the <i>in vitro</i> quantitative<br>determination of N-terminal<br>pro-brain natriuretic peptide in<br>human plasma as an aid in the<br>diagnosis of individuals suspected<br>of having congestive heart failure. | For the <i>in vitro</i> quantitative<br>determination of N-terminal pro-brain<br>natriuretic peptide in human serum<br>and plasma as an aid in the diagnosis<br>of individuals suspected of having<br>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 | 10 - 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 < 75 years;<br>450 pg/mL for patients ≥ 75 years | 125 pg/mL for patients < 75 years;<br>450 pg/mL for patients ≥ 75 years |
| Analytical<br>Sensitivity | ≤ 10 pg/mL | 5 pg/mL |
| Functional<br>Sensitivity | ≤ 30 pg/mL | < 50 pg/mL |
| Analytical<br>Specificity | The pharmaceutical Natrecor®<br>shows no significant cross reactivity<br>at 0 and 125 pg/mL NT-proBNP;<br>sixteen other substances show no<br>significant cross reactivity | The pharmaceutical Natrecor® shows<br>no significant cross reactivity at<br>300 pg/mL and 3000 pg/mL<br>NT-proBNP; sixteen other<br>substances show no significant cross<br>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 purified synthetic<br>NT-proBNP (1-76) | Roche purified synthetic<br>NT-proBNP (1-76) |
| Hook Effect | No high dose effect<br>( up to 300,000 pg/mL) | No high dose effect<br>( up to 300,000 pg/mL) |
| Calibration Interval | 30 days - same reagent lot | 30 days - same reagent lot |
| Sample Volume | 50 uL | 20 uL |

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# Method Performance Summary

## CLINICAL

For the Reference Study Group, NT-proBNP concentrations were determined in 308 individuals without congestive heart failure (163 women and 145 men); this population included apparently health individuals and individuals with diabetes, hypertension, and pulmonary disease. For the Disease Study Group, blood

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samples were obtained from 227 patients diagnosed with congestive heart failure (CHF); this population included 69 women and 158 men.

The high level of equivalence on clinical performance measures justifies using the cutoffs recommended for the predicate device, as shown below:

| Patients < 75 years: | 125 pg/mL [14.8 pmol/L] |
|----------------------|-------------------------|
| Patients ≥75 years: | 450 pg/mL [53.2 pmol/L] |

The clinical performance of the Dade Behring assay was substantially equivalent to that of the predicate device. Data used to calculate the values are from the method comparison and reference interval data sets generated at the University of Maryland Medical Center.

Clinical Performance of Dade Behring NT-proBNP assay vs. predicate device on Male patients.

| Males | | <75 yrs (95% CI) | ≥75 yrs (95% CI) |
|-----------------|-----------------|------------------|------------------|
| Sensitivity (%) | Dimension® PBNP | 84 (77 - 91) | 91 (84 - 99) |
| | Elecsys® proBNP | 90 (85 - 96) | 91 (84 - 99) |
| Specificity (%) | Dimension® PBNP | 94 (90- 99) | 77 (67-88) |
| | Elecsys® proBNP | 92 (87 - 98) | 73 (61 - 84) |
| NPV | Dimension® PBNP | 82 | 92 |
| | Elecsys® proBNP | 88 | 92 |

Clinical Performance of Dade Behring NT-proBNP assay vs. predicate device on Female patients.

| Females | | <75 yrs (95% CI) | ≥75 yrs (95% CI) |
|-----------------|-----------------|------------------|------------------|
| Sensitivity (%) | Dimension® PBNP | 77 (64 – 89) | 91 (79 – 100) |
| | Elecsys® proBNP | 81 (70–92) | 95 (87 – 104) |
| Specificity (%) | Dimension® PBNP | 93 (89–98) | 88 (80–96) |
| | Elecsys® proBNP | 91 (85–96) | 87 (78–95) |
| NPV | Dimension® PBNP | 91 | 96 |
| | Elecsys® proBNP | 92 | 98 |

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#### ANALYTICAL

Comparison using split patient heparinized plasma samples between the Dade Behring Dimension® PBNP Flex® method and the predicate Roche Elecsys® proBNP immunoassay demonstrated good agreement between the methods as summarized below:

| Method Correlation | | | | |
|-----------------------|-------|----------------------|----------------------------|-----|
| Comparative Method | Slope | Intercept<br>(pg/mL) | Correlation<br>Coefficient | n |
| Roche Elecsys® proBNP | 0.90 | -15.4 | 0.985 | 352 |

Model equation by Passing-Bablok linear regression statistics is: [results for Dimension = slope x [comparative method results] + intercept. The range of NT-proBNP values in the correlation study was: 16.1 to 29,893.1 pg/mL.

In addition, comparison of lithium heparin versus sodium heparin and EDTA plasma samples on the Dimension® system showed very good agreement. Lithium heparin samples ranging from 13 to 29,221 pg/mL when compared to sodium heparin and EDTA samples gave slopes of 0.95 and 0.96, correlation coefficients of 0.998 and 0.998, and intercepts of 0.9 and 10.9 respectively, using Passing-Bablok regression statistics.

#### Reproducibility

| | Mean (pg/mL) | Within-Run Precision | | Total Precision | |
|---------------------------------|--------------|----------------------|-----|-----------------|-----|
| | | SD (pg/mL) | %CV | SD (pg/mL) | %CV |
| Human Plasma Pool | | | | | |
| Pool 1 | 159.0 | 3.4 | 2.2 | 9.1 | 5.7 |
| Internal QC Pools | | | | | |
| Pool 1 | 449.5 | 8.1 | 1.8 | 16.6 | 3.7 |
| Pool 2 | 956.7 | 15.3 | 1.6 | 34.9 | 3.6 |
| AuditTM MicroFDTM BNP Control * | | | | | |
| Level 1 | 175.5 | 2.0 | 1.1 | 6.8 | 3.8 |
| Level 2 | 3733.8 | 71.8 | 1.9 | 115.9 | 3.1 |

Typical precision observed for the Dimension® PBNP Flex® method is summarized below:

The reproducibility testing was done in accordance with the NCCLS Approved Guideline for User Evaluation of Precision Performance of Clinical Chemistry Devices EP5-A, 1999. Specimens at each level were analyzed in duplicate once per day for 20 days. The within-run and total standard deviations were calculated by the analysis of variance method.

- * Audit™ and MicroFD™ are registered trademarks of Audit™ MicroControls, Inc., Las Vegas, NV

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#### 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/K022516) are substantially equivalent based on their intended use and performance characteristics as described above. The calibrator products are also equivalent in their design and intended use with their respective assay systems.

> Richard M. Vaught Regulatory Affairs and Compliance Manager May 26, 2004

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Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Mr. Richard M. Vaught Regulatory Affairs and Compliance Manager Dade Behring Inc. P.O. Box 6101 Newark, DE 19714

JUL 2 0 2004

Re: k041417

> Trade/Device Name: Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method Dimension® PBNP Calibrator Regulation Number: 21 CFR 862.1117 Regulation Name: B-type natriuretic peptide test system Regulatory Class: Class II Product Code: NBC, JIT Dated: May 26, 2004 Received: May 27, 2004

Dear Mr. Vaught:

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 (OS) 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,

Jean M. Cooper, MS, DVM.

Tean M. Cooper, MS, D.V.M. 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 STATEMENT

#### Device(s) Name(s):

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

#### Indications for Use:

The Dade Behring Dimension® PBNP Flex® reagent cartridge 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.

The Dade Behring Dimension® PBNP Calibrator is intended to be used to calibrate the N-terminal pro-brain natriuretic peptide (PBNP) method for the Dade Behring Dimension® clinical chemistry system.

RmVaught
Richard M. Vaught

Richard M. Vaught Regulatory Affairs and Compliance Manager

May 26, 2004

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)

Aleat Catz

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) k041117

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