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.

Device Description

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.

AI/ML Overview

Acceptance Criteria and Device Performance Study for Dade Behring Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method

This document summarizes the acceptance criteria and the study demonstrating the Dade Behring Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method meets these criteria, based on the provided FDA 510(k) summary. The device's performance is demonstrated through a comparison to a legally marketed predicate device, the Roche Diagnostics Elecsys® proBNP immunoassay, to establish substantial equivalence.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the Dade Behring Dimension® PBNP Flex® method are implicitly defined by demonstrating substantial equivalence to the predicate device, the Roche Diagnostics Elecsys® proBNP immunoassay, across various performance characteristics. The reported device performance is directly compared to the predicate's performance.

Feature	Acceptance Criteria (Predicate Device Performance - Roche Elecsys® proBNP)	Reported Device Performance (Dade Behring Dimension® PBNP)
Intended Use	Quantitative determination of NT-proBNP in human serum and plasma as an aid in diagnosis of suspected CHF and risk stratification of ACS and CHF patients.	Quantitative determination of NT-proBNP in human plasma as an aid in diagnosis and severity assessment of suspected CHF and for risk stratification of ACS and CHF patients.
Assay Type (detection)	immunoassay (electrochemiluminescent)	immunoassay (photometric)
Reportable Range	5 - 35,000 pg/mL	5 - 30,000 pg/mL
Antibody	polyclonal (sheep) antibody	Roche Diagnostics' polyclonal (sheep) antibody
Cut-off	125 pg/mL for < 75 years, 450 pg/mL for ≥ 75 years	125 pg/mL for < 75 years, 450 pg/mL for ≥ 75 years
Analytical Sensitivity	5 pg/mL	≤ 10 pg/mL
Functional Sensitivity	< 50 pg/mL	≤ 30 pg/mL
Analytical Specificity	Natercor® shows no significant cross-reactivity (300/3000 pg/mL NT-proBNP); 16 other substances show no significant cross-reactivity.	Natercor® shows no significant cross-reactivity (0/125 pg/mL NT-proBNP); 16 other substances show no significant cross-reactivity.
Interferences	No significant interference from: bilirubin up to 35 mg/dL, hemoglobin up to 1.4 g/dL, triglycerides up to 4000 mg/dL, rheumatoid factors up to 1500 IU/mL.	No significant interference from: bilirubin (conj. up to 60 mg/dL, unconj. up to 20 mg/dL), hemoglobin up to 1000 mg/dL, triglycerides up to 3000 mg/dL, rheumatoid factors up to 500 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	20 uL	50 uL
Reproducibility (Within Run)	1.8% - 2.7% CV across various concentrations	1.2% - 2.2% CV across various concentrations
Reproducibility (Total)	2.2% - 3.2% CV across various concentrations	3.1% - 5.7% CV across various concentrations

2. Sample Size for the Test Set and Data Provenance

The document states, "Comparative data for human plasma samples demonstrate good analytical and clinical agreement between the methods." However, the specific sample size used for the test set is not explicitly provided in the furnished text.

The data provenance is stated as "human plasma samples." Without further detail, it is impossible to determine the country of origin of the data or whether it was retrospective or prospective.

3. Number of Experts and Qualifications for Ground Truth

This information is not explicitly provided in the furnished text. This being an in vitro diagnostic (IVD) device for quantitative measurement, "ground truth" typically refers to established values from reference methods, calibrators, or clinically validated samples rather than expert consensus on image interpretation. The study appears to rely on the predicate device as a "gold standard" for comparison.

4. Adjudication Method

Adjudication methods (e.g., 2+1, 3+1) are not typically applicable or mentioned for IVD device studies focusing on quantitative measurements and analytical agreement. The study focuses on direct comparison of measurements between the investigational device and the predicate device.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for imaging devices or diagnostics where human interpretation plays a significant role. The Dade Behring Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method is an automated in vitro diagnostic assay, where human "readers" are not directly involved in interpreting the result; rather, clinicians interpret the quantitative output in the context of a patient's condition. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply here.

6. Standalone Performance

Yes, a standalone performance assessment was conducted. The performance characteristics (e.g., reportable range, analytical sensitivity, functional sensitivity, reproducibility, interference) detailed in the comparison table are inherently measurements of the device's standalone performance. These are the characteristics of the algorithm/method itself as it processes samples to produce a quantitative result. The comparison to the predicate then serves to demonstrate that this standalone performance is substantially equivalent to a legally marketed device.

7. Type of Ground Truth Used

The "ground truth" for this study is effectively the results obtained from the predicate device (Roche Diagnostics Elecsys® proBNP immunoassay). The study's primary objective is to demonstrate substantial equivalence to this predicate, suggesting that the predicate's performance represents the acceptable "truth" or standard against which the new device is measured. This is supported by the statement: "Comparative data for human plasma samples demonstrate good analytical and clinical agreement between the methods."

8. Sample Size for the Training Set

The sample size for the training set is not explicitly provided in the furnished text. As this is an immunoassay, the "training set" would typically refer to samples used during the development and optimization of the assay's reagents, calibration curves, and analytical parameters. This is distinct from a "training set" in machine learning contexts.

9. How the Ground Truth for the Training Set was Established

The method for establishing "ground truth" for the training set is not explicitly detailed in the furnished text. During the development of an immunoassay, the "ground truth" for training (i.e., assay optimization and calibration) would generally involve:

Reference standards: Using highly purified and well-characterized NT-proBNP material to create calibrators with known concentrations.
Spiked samples: Adding known concentrations of NT-proBNP to biological matrices to assess recovery and linearity.
Comparison to existing methods: Utilizing established and validated methods (potentially the predicate itself or other reference methods) on a set of samples to refine the new assay's performance.

Given that the device "utilizes the Roche polyclonal (sheep) antibody/antigen set," it is likely that the development and "training" process leveraged existing knowledge and materials associated with the predicate's core components.

Summary

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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. PlummerDade Behring Inc.P.O. Box 6101Newark, 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 NatriureticPeptide Premarket Notifications; Final Guidance for Industry andFDA Reviewers" - 11/30/2000
Predicate Device(s):	Roche Diagnostics Elecsys® proBNP immunoassay(K022516/K032646)

Device Description(s):

Method

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

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Intended Use:

Method

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(K041417)	Roche Elecsys® proBNP(K032646/K022516)
Intended Use	For the in vitro quantitativedetermination of N-terminalpro-brain natriuretic peptide inhuman plasma as an aid in thediagnosis and assessment ofseverity of individuals suspected ofhaving congestive heart failure.The test is further indicated for therisk stratification of patients withacute coronary syndrome and heartfailure.	For the in vitro quantitativedetermination of N-terminalpro-brain natriuretic peptide in humanserum and plasma as an aid in thediagnosis of individuals suspected ofhaving congestive heart failure.The test is further indicated for therisk stratification of patients withacute coronary syndrome andcongestive heart failure.
Assay Type(detection)	immunoassay(photometric)	immunoassay(electrochemiluminescent)
Reportable Range	5 - 30,000 pg/mL	5 - 35,000 pg/mL
Antibody	Roche Diagnostics'polyclonal (sheep) antibody	polyclonal (sheep) antibody
Cut-off	125 pg/mL for patients less than 75years and 450 pg/mL for patients 75years and older	125 pg/mL for patients less than 75years and 450 pg/mL for patients 75years and older
Feature	Dimension® PBNP(K041417)	Roche Elecsys® proBNP(K032646/K022516)
AnalyticalSensitivity	≤ 10 pg/mL	5 pg/mL
FunctionalSensitivity	≤ 30 pg/mL	< 50 pg/mL
AnalyticalSpecificity	Natercor® shows no significantcross reactivity,0 or 125 pg/mL NT-proBNP; sixteen other substancesshow no significant cross reactivity	Natercor® shows no significant crossreactivity, 300 pg/mL or 3000 pg/mLNT-proBNP; sixteen other substancesshow no significant cross reactivity
Interferences	No significant interference from:bilirubin ,conj. up to 60 mg/dLbilirubin, unconj. up to 20 mg/dLhemoglobin up to 1000 mg/dLtriglycerides up to 3000 mg/dLrheumatoid factors up to 500 IU/mL	No significant interference from:bilirubin up to 35 mg/dLhemoglobin up to 1.4 g/dLtriglycerides up to 4000 mg/dLrheumatoid 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 Run2.2 % CV @ 159 ng/mL1.8% CV @ 484.31.6% @ 1037.8 ng/mL1.2% CV @ 184.7 ng/mL1.9% CV @ 4062.4 ng/mLTotal5.7 % CV @ 159 ng/mL3.7% CV @ 484.33.7% @ 1037.8 ng/mL4.0% CV @ 184.7 ng/mL3.1% CV @ 4062.4 ng/mL	Within Run2.7% CV @ 175 ng/mL2.4% CV @ 355 ng/mL1.8% CV @ 434 ng/mL1.9% CV @ 1068 ng/mL1.8% CV @ 4962 ng/mL1.8% CV @ 6781 ng/mLTotal3.2% CV @ 175 ng/mL2.9% CV @ 355 ng/mL2.6% CV @ 434 ng/mL2.3% CV @ 1068 ng/mL2.4% CV @ 4962 ng/mL2.2% CV @ 6781 ng/mL

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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) 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

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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).

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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 (301) 594-3084. 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 (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.

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

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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
(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

Regulation Number and Section

§ 862.1117 B-type natriuretic peptide test system.

(a)
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.(b)
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.”