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.

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.

AI/ML Overview

The Bayer Diagnostics ADVIA Centaur BNP Assay is an in vitro immunoassay designed for the quantitative determination of B-type Natriuretic Peptide (BNP) in human plasma, to be used as an aid in the diagnosis of heart failure.

1. A table of acceptance criteria and the reported device performance

The provided text describes comparative performance against a predicate device and clinical agreement, rather than explicit pre-defined acceptance criteria with pass/fail thresholds. However, based on the comparative effectiveness study, we can infer the desired performance characteristics.

Performance Characteristic	Implicit Acceptance Criteria (Inferred)	Reported Device Performance (ADVIA Centaur® BNP Immunoassay)
Analytical Agreement	High agreement with predicate device (Biosite Triage® BNP Test) at the 100 pg/mL decision threshold.	94.7% (177/187) with a 95% Confidence Interval of 90.4% to 97.4%.
Clinical Agreement	High overall agreement with clinical diagnosis (HF vs. non-HF) at the 100 pg/mL decision threshold.	87.2% (163/187) with a 95% Confidence Interval of 81.5% to 91.6%. The predicate device showed 86.1% clinical agreement.
Sensitivity	High sensitivity for detecting heart failure at the 100 pg/mL decision threshold.	87.4% (146/167) with a 95% Confidence Interval of 81.4% to 92.0%. This is identical to the predicate device's sensitivity.
Specificity	Good specificity for not misidentifying non-heart failure patients as heart failure at the 100 pg/mL decision threshold.	85.0% (17/20) with a 95% Confidence Interval of 62.1% to 96.8%. This is higher than the predicate device's specificity of 75.0%.
Precision	Comparable or better precision than the predicate device.	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. (Predicate: Average within-day 9.4 - 15.2 %CV; Average total 10.1 - 16.2 %CV). The ADVIA Centaur shows significantly better precision.
Analytical Sensitivity	Low detection limit.	<2 pg/mL (Predicate: 5 pg/mL). The ADVIA Centaur has a lower detection limit.
Measuring Range	Broad measuring range to cover clinically relevant levels.	<2.0 - 5000 pg/mL (Predicate: 5 - 5000 pg/mL). The ADVIA Centaur covers a similar range with a lower minimum detection.
Interference	No significant interference from common substances/drugs.	For the ADVIA Centaur, no interference was observed from: hemoglobin up to 1000 mg/dL, triglycerides up to 800 mg/dL, cholesterol up to 1000 mg/dL, urea up to 200 mg/dL, creatinine up to 2.5 mg/dL, unconjugated bilirubin up to 25 mg/dL, conjugated bilirubin up to 25 mg/dL, human IgG up to 5.3 g/dL, and 55 commonly used pharmaceutical drugs.

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

Sample Size for Test Set: 187 patients. This includes 167 patients with heart failure (HF; clinical diagnoses of Class I – IV) and 20 individuals without heart failure (non-HF).
Data Provenance: Not explicitly stated whether the data was retrospective or prospective, nor the country of origin. It was collected from "2 clinical trial sites."

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

The ground truth for the test set was clinical diagnoses of heart failure ("clinical diagnoses of Class I – IV"). The number and qualifications of experts involved in establishing these clinical diagnoses are not specified in the provided text.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

The text does not mention any specific adjudication method for establishing the clinical diagnoses (ground truth). It simply refers to "clinical diagnoses."

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This study is for an in vitro diagnostic (IVD) assay, not an AI-assisted diagnostic tool that would typically involve human readers.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, this study represents the standalone performance of the ADVIA Centaur BNP assay. It is an automated immunoassay where the algorithm (the assay and instrument system) determines the BNP levels without human interpretation of raw data beyond operating the instrument and collecting the results. The "performance characteristics" and "analytical/clinical agreement" tables directly reflect the standalone performance of the device.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth used for evaluating clinical agreement was clinical status (clinical diagnosis of heart failure vs. non-heart failure). For analytical comparison, the ground truth was the results from the predicate device.

8. The sample size for the training set

The text does not provide information about a separate training set or its sample size. This document describes the performance evaluation of a device, not the development or training of a machine learning model.

9. How the ground truth for the training set was established

As there is no mention of a training set, the method for establishing its ground truth is not applicable/not provided.

Summary

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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 Corporation511 Benedict Ave.Tarrytown, N.Y. 10591
	Phone: (914) 524 2446Fax: (914) 524 2500e-mail: ken.edds.b@bayer.com
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

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® BNPImmunoassay	Biosite Triage® BNP Test(Predicate Device)
Intended Use	Quantitative determination of B-type Natriuretic Peptide	Measurement of B-typeNatriuretic Peptide
Indication for Use	An aid in the diagnosis of heartfailure.	An aid in the diagnosis ofcongestive heart failure.
Assay Principle	Chemiluminescenceimmunoassay	Fluorescence immunoassay
Traceability/Standardization	• Reference standard - synthetichuman BNP (amino acid 77 to108) in buffer based matrix.	Purified protein preparation ofBNP based on the mass(concentration) of analytepresent in EDTA plasma.

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Feature	Bayer ADVIA Centaur® BNPImmunoassay	Biosite Triage® BNP Test(Predicate Device)
Calibration Interval	• After 28 days when using thesame reagent lot• With every new primaryreagent lot	Each kit
Sample Type	Human plasma using EDTA asanticoagulant	Human whole blood and plasmausing 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• Until the expiration date whenstored at 2-8°COnboard• 41.6 days (or 60 days with theuse of version 3.0 software orhigher)	• Until the expiration date whenstored at 2-8°C• 14 days at room temperature
Instrument	ADVIA Centaur System, a fullyautomated, random-accessimmunoassay 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® BNPImmunoassay	Biosite Triage® BNP Test(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® BNPImmunoassay	Biosite Triage® BNP Test(Predicate Device)
	sodium citrate, lithium heparinand sodium fluoride sampletubes have also been testedand are not recommended.• No interference fromhemoglobin up to 1000 mg/dL• No interference fromtriglycerides up to 800 mg/dL• No interference fromcholesterol up to 1000 mg/dL• No interference from urea upto 200 mg/dL• No interference fromcreatinine up to 2.5 mg/dL• No interference fromunconjugated bilirubin up to25 mg/dL• No interference fromconjugated bilirubin up to25 mg/dL• No interference from humanIgG up to 5.3 g/dL• No interference from 55commonly usedpharmaceutical drugs.• Results should always beassessed in conjunction withthe patient's medical history,clinical evaluation and otherdiagnostic procedures.	anticoagulant. Serum andblood or plasma specimensobtained using otheranticoagulants (e.g. heparinor citrate) have not beenevaluated and should not beused.• No interference fromhemoglobin up to10000 mg/dL• Severely hemolyzedspecimens should be avoided• No interference fromtriglycerides up to 1000 mg/dL• No interference fromcholesterol up to 1000 mg/dL• No interference from bilirubinup to 20 mg/dL• No interference from 55commonly usedpharmaceutical drugs.• Results should be evaluatedin the context of all the clinicaland 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
PredicateDevice	≥ 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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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 (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,

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:

Dean Cooper

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K031038

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

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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.”