I-STAT B-TYPE NATRIURETIC PEPTIDE (BNP)

K053597 · I-Stat Corporation · NBC · Jul 21, 2006 · Clinical Chemistry

Device Facts

• Record ID: K053597
• Device Name: I-STAT B-TYPE NATRIURETIC PEPTIDE (BNP)
• Applicant: I-Stat Corporation
• Product Code: NBC · Clinical Chemistry
• Decision Date: Jul 21, 2006
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Intended Use

The i-STAT BNP test is an in vitro diagnostic test for the quantitative measurement of B-type natriuretic peptide (BNP) in whole blood or plasma samples using EDTA as the anticoagulant. BNP measurements can be used as an aid in the diagnosis and assessment of severity of congestive heart failure. The i-STAT Controls are assayed liquid plasma used to verify the integrity of newly received i-STAT BNP cartridges. The i-STAT BNP Calibration Verification Controls are assayed liquid plasma used to verify the calibration of i-STAT BNP cartridges throughout the reportable range.

Device Story

i-STAT BNP test is a single-use cartridge-based assay for quantitative BNP measurement in whole blood or plasma. Operates on i-STAT 1 Analyzer; requires EDTA anticoagulant. Cartridge contains electrochemical sensors on silicon chip; utilizes two-site ELISA principle. Sample introduced to cartridge; BNP captured by antibody-enzyme conjugate; enzyme cleaves substrate to produce electrochemically detectable product proportional to BNP concentration. Used in clinical settings; provides rapid quantitative results to assist physicians in diagnosing and assessing congestive heart failure severity. System includes automated self-checks for sensor performance, fluid integrity, and thermal/pressure transducers; results suppressed if deviations occur. Calibration is factory-set.

Clinical Evidence

Clinical evidence derived from studies using Abbott AxSYM BNP assay to support reference range transfer. Study population included 890 non-heart failure individuals and 693 heart failure patients (NYHA classes I-IV). AUC for heart failure diagnosis is 0.90 (95% CI: 0.86-0.92) at 100 pg/mL threshold. Clinical sensitivity 74.2%, specificity 91.5%. Method comparison with ARCHITECT assay (n=433) showed correlation slope of 0.97 and r=0.961.

Technological Characteristics

Two-site ELISA; electrochemical (amperometric) detection. Cartridge contains silicon chip with electrochemical sensors, antibody/alkaline phosphatase conjugate, buffer, and preservatives. Sample type: EDTA whole blood or plasma. Factory-set calibration. Dimensions/form factor: single-use cartridge for i-STAT 1 Analyzer. No optical interferents due to electrochemical detection.

Indications for Use

Indicated for quantitative measurement of BNP in whole blood or plasma (EDTA) to aid in diagnosis and severity assessment of congestive heart failure in patients. For use by trained healthcare professionals.

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

• Biosite Triage BNP Test (k021317)

Reference Devices

• Abbott ARCHITECT BNP test

Submission Summary (Full Text)

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K053597

# 510(k) Summary

This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1900 and CFR 807.92.

The assigned 510(k) number is:

#### Summary prepared on: December 9, 2005

#### Submitted by:

i-STAT Corporation 104 Windsor Center Drive E. Windsor, NJ 08520 Phone: [phone] FAX: [phone]

#### Contact:

Sue Kent - Manager, Clinical Affairs i-STAT Corporation 104 Windsor Center Drive East Windsor, NJ 08520 Phone: [phone] Fax: [phone] Email: [e-mail]

#### Establishment Registration Number: 2245578

### ldentification of Device:

Test:

Device Name: i-STAT® BNP Test Proprietary/Trade Name: i-STAT® BNP Test Common Name: BNP, B-Type Natriuretic Peptide Device Classification: II Regulation Number: CFR§ 862.1117 Panel: B-Type Natriuretic Peptide Test System Product Code: NBC

#### Controls/calibration verification controls:

Device Name: i-STAT® BNP Control Level 1 i-STAT® BNP Control Level 2 i-STAT® BNP Control Level 3 i-STAT® BNP Calibration Verification Control Set Proprietary/Trade Name: i-STAT® BNP Control Level 1 i-STAT® BNP Control Level 2 i-STAT® BNP Control Level 3 i-STAT® BNP Calibration Verification Control Set Common Name: BNP controls, BNP calibration verification controls Device Classification: I Regulation Number: 21 CFR§ 862.1660 Panel: Single (Specified) Analyte Controls (Assayed and Unassayed)

Product Code: JJX

#### Identification of the Predicate Device: Test:

Device Name: BNP test for use on the Biosite Triage® Meter.

Controls/calibration verification controls:

Device Name: Triage® BNP Calibration Verification Controls

JUL 2 1 2006

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#### Intended Use of the Device: Test:

The i-STAT BNP test is an in vitro diagnostic test for the quantitative measurement of B-twpe natriurelic peptide (BNP) in whole blood or plasma samples using EDTA as the anticoagulant. BNP measurements can be used as an aid in the diagnosis and assessment of the severity of congestive heart failure.

The cartridge is to be used with the i-STAT 1 Analyzer bearing the (Immuno) symbol, but not with the i-STAT Portable Clinical Analyzer or the Philips Medical Systems (formerly Agilent Technologies) Blood Analysis Module (BAM). As part of the i-STAT System, the BNP test is to be used by trained health care professionals in accordance with a facility's policies and procedures.

#### Controls:

The i-STAT BNP Controls are assayed liquid plasma used to verify the integrity of newly received i-STAT BNP cartridges.

#### Calibration verification controls:

The i-STAT BNP Calibration Verification Controls are assayed liguid plasma used to verify the calibration of i-STAT BNP cartridges throughout the reportable range.

### Description of the Device:

#### Test:

The i-STAT BNP test is contained in a single-use test cartridge. In use, the user scans a bar code and then places approximately 17 u of whole blood or plasma in the cartridge. After the cartridge is closed, it is inserted into the thermally controlled i-STAT 1 Analyzer, and all analytical steps are performed automatically. Patient and use information may be entered into the analyzer via a keypad during the automated analysis cycle.

As the analyzer performs several quality checks and controls the temperature of the sensors via resistive heating to the underside of the sensor chips, the substrate/wash fluid is released into a conduit within the cartridge and a metered volume of the sample over the sensor chips. The enzyme-linked antibody conjugate dissolves into the sample incubates for a controlled time. The sample is then pushed into a waste chamber and the substrate/wash solution is brought over the sensors. The alkaline phosphatase captured on the BNP sensor cleaves the substrate present in the substrate/wash fluid, giving rise to an amperometric signal that is measured.

#### Controls:

The i-STAT BNP Controls are supplied in three levels packaged as six vials of one level per box with each vial containing 1 mL of control material. The three levels are in frozen liquid form, require no reconstitution or dilution, and are each comprised of a different level of BNP, a chemical synthetic peptide, prepared in human EDTA plasma and preserved with sodium azide. The first level of BNP is set at a typical diagnostic cutoff level while the second and third are set at higher levels spanning the range of the test. The BNP value will be provided in the value assignment sheet for each level.

#### Calibration verification controls:

The i-STAT BNP Calibration Verification Control Set is packaged as a tri-level set comprised of two vials of each of three levels per box. The three levels in the BNP Calibration Verification Control Set are exactly the same materials as those used in the Level 1, Level 2, and Level 3 control products. The only difference between this product and the i-STAT BNP Controls is the number of vials and the number of levels that are packaged together.

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# Comparison to Technological Features of the Predicate Device:

The following is a comparison of technological features of the i-STAT and Biosite Triage BNP test methods:

| Characteristic | Triage BNP | I-STAT BNP |
|-----------------------|----------------------------|----------------------------|
| Assay methodology | Two-site ELISA | Two-site ELISA |
| Capture site | Heterogeneous | Heterogeneous |
| Capture antibodies | Monoclonal | Monoclonal |
| Enzyme label antibody | Monoclonal | Monoclonal |
| Enzyme label | Fluorescent dye | Alkaline phosphatase |
| Analysis sequence | Simultaneous capture/label | Simultaneous capture/label |
| Analysis time | 15 minutes | 10 minutes |
| Sample type | Whole blood or plasma | Whole blood or plasma |
| Enzyme detection | Fluorescent | Electrochemical |

The similarities and differences between the i-STAT controls products and the Biosite Triage BNP control products can be seen in the table below:

| Characteristics | Triage BNP Calibration<br>Verification Controls<br>(predicate device) | i-STAT BNP Control<br>Level 1, 2, & 3 and<br>i-STAT BNP Calibration<br>Verification Control Set<br>(new device) |
|--------------------|-----------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------|
| Similarities | | |
| Matrix | Human Plasma | Human Plasma |
| Form | Frozen liquid | Frozen liquid |
| Analytes | BNP (assayed) | BNP (assayed) |
| Number of Levels | Three | Three |
| Differences | | |
| Opened Vial Claim | Tested same day as thaw | 4 hours when stored at 2 to 8°C |
| Vial | Plastic vial with screw top lid | 10 mL plastic vial with dropper-top |
| Fill volume | 0.5 ml | 1 ml |
| Storage (unopened) | ≤ -20°C<br>until expiration date | ≤ -18°C<br>until expiration date |

# Summary of Performance in Support of Substantial Equivalence:

Test:

- Studies established that the i-STAT BNP test is insensitive to hematocrit levels from 0 to 60 . %PCV.
- . The i-STAT BNP assay is not significantly influenced by the presence of NT-pro-BNP, ANP or CNP at 1000 pg/mL or 20,000 pg/mL.
- Studies established that there are no significant interference effects on the i-STAT BNP test . from common medications, particularly those commonly prescribed to patients with cardiovascular conditions.
- . Studies established that the lower limit of detection (LLD) for the i-STAT method is 15 pg/mL versus 5.0 pg/mL for the Triage BNP test.
- . The imprecision of the i-STAT BNP test using plasma controls was established using in-house studies. The Level 1 Control %CV was 11.1% at 126 pg/mL; the Level 2 Control %CV was 8.1% at 1551 pg/mL, and the Level 3 Control %CV was 9.8% at 3337 pg/mL. This includes within-lot, lot-to-lot, vial-to-vial, analyzer-to-analyzer, and operator-to-operator components of the imprecision.

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Studies conducted in-house compared the results of the i-STAT BNP test to those of the BNP test on the Abbott ARCHITECT. EDTA-anticoagulated samples were analyzed on both systems. The methods were compared using Deming regression analysis. The results are summarized in the table below:

| Statistic | Definition | i-STAT vs. Abbott ARCHITECT | |
|-------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|-------------------------------------|
| | | all samples | samples where<br>$[BNP]$ <400 pg/mL |
| N | The number of patient<br>samples included in<br>the data set | 433 | 312 |
| Mean | The average of the<br>comparative method<br>result over the<br>sample population | 482.1 | 51.9 |
| Range | The range of<br>comparative method<br>results obtained over<br>the sample population | 5.0 - 4797.7 | 5.0 - 400.0 |
| Sxx | The pooled estimate<br>of the within-sample<br>standard deviation of<br>the comparative<br>method over the<br>sample population | 38.1 | 7.2 |
| Syy | The pooled estimate<br>of the within-sample<br>standard deviation of<br>the test method over<br>the sample population | 97.6 | 11.5 |
| Slope | The Deming slope of<br>the correlation | 0.971 | 1.13 |
| Intercept | The Deming intercept<br>of the correlation | -14.4 | -7.3 |
| Correlation | The correlation<br>coefficient determined<br>from regression | 0.972 | 0.964 |
| Sy.x | The standard error of<br>the estimate of the<br>regression of the<br>regression of y (test<br>method) on x<br>(comparative method)<br>calculated using the<br>regular regression<br>slope | 198.0 | 25.7 |

# Controls/calibration verification controls:

- The within-level vial-to-vial imprecision for all three levels of the i-STAT BNP controls was . found to range from 0.8% to 5.8% testing three lots of each control level.
- . Studies demonstrated that all three levels meet the claim of 4 hours' stability after the product has been thawed.

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## Conclusions:

#### Test:

Based on the data, the i-STAT BNP test is insensitive to hematocrit level from 0 – 60 %PCV, is not significantly influenced by the presence of related peptides, shows no significant interference effects to common drugs, and has a comparable lower limit of detection (LLD) as the Biosite Triage BNP. Studies using plasma controls indicate adequate imprecision for low, mid-range, and high results. Clinical data indicates acceptable correlation to the predicate device.

#### Controls/calibration verification controls:

The i-STAT BNP Controls Level 1, Level 2, and Level 3, and the i-STAT BNP Calibration Verification Control Set are substantially equivalent to the previously cleared Triage® BNP Calibration Verification Controls as indicated by the data.

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## DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services (HHS). The logo features a stylized caduceus, a symbol often associated with medicine and healthcare, with three parallel lines forming a stylized human figure. The caduceus is encircled by the words "U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES" in a circular arrangement.

Re:

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Paul VanDerWerf, Ph.D. Director, Regulatory Affairs i-STAT Corporation 104 Windsor Center Drive East Windsor, NJ 08520

JUL 2 1 2006

k053597 Trade/Device Name: i-STAT BNP test i-STAT BNP Control Level 1 i-STAT BNP Control Level 2 i-STAT BNP Control Level 3 i-STAT BNP Calibration Verification Control Set Regulation Number: 21 CFR8862.1117 Regulation Name: B-type natriuretic peptide test system Regulatory Class: Class II Product Code: NBC, JJX Dated: June 14, 2006 Received: June 15, 2006

Dear Dr. VanDerWerf

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 [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 vours.

Alberto G

Alberto Gutierrez, Ph.D. 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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# 3 a. Indications for use

510(k) Number (if known):

K05 3597

Device Name: i-STAT BNP test

The i-STAT BNP test is an in vitro diagnostic test for the quantitative measurement of B-Type Natriuretic Peptide (BNP) in whole blood or plasma samples using EDTA as the anticoagulant. BNP measurements can be used as an aid in the diagnosis and assessment of the severity of congestive heart failure.

Prescription Use
(Part 21 CFR 801 Subpart D)
o

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 In Vitro Diagnostic Devices (OIVD)

Carol C. Benson
Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safet

K053597

Page 1 of

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# b. Indications for use ಳು 510(k) Number (if known):

Device Names: i-STAT BNP Control Level 1 i-STAT BNP Control Level 2 i-STAT BNP Control Level 3

The i-STAT BNP Controls are assayed liquid plasma used to verify the integrity of newly received i-STAT BNP cartridges.

AND/OR Over-The-Counter Use Prescription Use (21 CFR 801 Subpart C) (Part 21 CFR 801 Subpart D) 0 (PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

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

Carl Benson

Vision Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safe

K053597

Page 2 of 2

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# 3 c. Indications for use

510(k) Number (if known):

# Device Name: i-STAT BNP Calibration Verification Control Set

The i-STAT BNP Calibration Verification Controls are assayed liquid plasma used to verify the calibration of i-STAT BNP cartridges throughout the reportable range.

(Prescription Use (Part 21 CFR 801 Subpart D)

O

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 In Vitro Diagnostic Devices (OIVD)

Carol C. Benson
Vision Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

K053597

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