(45 days)
The Stratus® CS Acute Care™ NT-proBNP method (pBNP) 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 NTproBNP 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. This method is for use by trained health care professionals on the Stratus® CS Stat Fluorometric Analyzer in the clinical laboratory and point of care (POC) settings.
The Stratus® CS Acute Care™ NT-proBNP method is a two-site sandwich assay based upon solid phase Radial Partition Immunoassav (RPIA) technology. In this procedure, dendrimer linked monoclonal antibody is added to the center portion of a square piece of glass fiber paper in the pBNP TestPak. This antibody recognizes a distinct antigenic site on the NT-proBNP molecule. Sample is then added onto the paper where it reacts with the immobilized antibody. After a short incubation, a conjugate consisting of enzyme-labeled monoclonal antibody directed against a second distinct antigenic site on the NT-proBNP molecule is pipetted onto the reaction zone of the paper. During this second incubation period, enzyme-labeled antibody reacts with the bound NT-proBNP, forming an antibody-antigen-labeled antibody sandwich. The unbound labeled antibody is later eluted from the field of view of the Stratus® CS analyzer by applying a substrate wash solution to the center of the reaction zone. By including substrate for the enzyme within the wash solution, initiation of enzyme activity occurs simultaneously with the wash. The enzymatic rate of the bound fraction increases directly with the concentration of NT-proBNP in the sample. The reaction rate can then be measured by an optical system that monitors the reaction rate via front surface fluorescence: All data analysis functions are performed by the microprocessor within the analyzer.
Acceptance Criteria and Device Performance for Stratus® CS Acute Care™ NT-proBNP (pBNP) TestPak (K071834)
The Stratus® CS Acute Care™ NT-proBNP (pBNP) TestPak is an in vitro diagnostic test for the quantitative measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) in heparanized plasma. It is intended to aid in the diagnosis and assessment of severity of congestive heart failure (CHF) and for risk stratification of patients with acute coronary syndrome and heart failure.
This 510(k) submission (K071834) seeks to demonstrate substantial equivalence to the previously cleared Dade Behring Stratus® CS Acute Care™ NT-proBNP (pBNP) (K043476/K060548) predicate device, primarily addressing a change in the antibody used (from polyclonal to monoclonal). The acceptance criteria and supporting studies are therefore focused on demonstrating comparable performance to the predicate device.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implicitly defined by the demonstration of "good agreement" and "very good agreement" with the predicate device, as well as meeting specific analytical performance characteristics.
| Acceptance Criteria / Performance Characteristic | Predicate Device Performance (Implicit Acceptance) | Revised Device Performance (Reported and Meets Acceptance) |
|---|---|---|
| Method Comparison (vs. Predicate) | - | Correlation: |
| Slope | - | 1.02 |
| Intercept (pg/mL) | - | 8.2 |
| Correlation Coefficient | - | 0.99 |
| Lithium Heparin vs. Sodium Heparin Comparison | - | Agreement: |
| Slope | - | 1.06 |
| Intercept (pg/mL) | - | -75 |
| Correlation Coefficient | - | 0.997 |
| Analytical Sensitivity | ≤15 pg/mL | ≤15 pg/mL |
| Functional Sensitivity | ≤ 50 pg/mL | ≤ 50 pg/mL |
| Analytical Specificity (Natrecor®) | No significant cross reactivity at 0 and 125 pg/mL NT-proBNP | No significant cross reactivity at 0 and 125 pg/mL NT-proBNP |
| Analytical Specificity (Other substances) | Sixteen other substances show no significant cross reactivity | Sixteen other substances also show no significant cross reactivity |
| Interferences (Bilirubin, Hemoglobin, Lipemia, Rheumatoid Factors) | No significant interference within specified limits (e.g., bilirubin up to 60 mg/dL, hemoglobin up to 1000 mg/dL, triglycerides up to 3000 mg/dL, rheumatoid factors up to 750 IU/mL) | No significant interference within specified limits (e.g., bilirubin up to 60 mg/dL, hemoglobin up to 1000 mg/dL, lipemia up to 3000 mg/dL, rheumatoid factors up to 500 IU/mL) |
| Hook Effect | No high dose effect (up to 1,400,000 pg/mL) | No high dose effect (up to 833,585 pg/mL) |
| Reportable Range | 15- 20,000 pg/mL | 15- 20,000 pg/mL |
| Cut-off | 125 pg/mL (<75 years), 450 pg/mL (>=75 years) | 125 pg/mL (<75 years), 450 pg/mL (>=75 years) |
2. Sample Sizes and Data Provenance for Test Set
-
Method Comparison Test Set:
- Sample Size: 148 patient samples.
- Data Provenance: Not explicitly stated, but clinical samples would typically be from the country where the study was conducted (presumably the US, given the FDA submission). The samples were "heparinized plasma patient samples," implying they were retrospective or prospective samples collected from patients. The document does not specify if it was retrospective or prospective.
-
Lithium Heparin versus Sodium Heparin Comparison Test Set:
- Sample Size: 51 samples, tested in duplicate.
- Data Provenance: Not explicitly stated, but likely from a similar clinical setting as the method comparison samples. The document does not specify if it was retrospective or prospective.
3. Number of Experts and Qualifications for Ground Truth for the Test Set
Not applicable. The study is a method comparison against a predicate device, not a diagnostic accuracy study where independent expert interpretation of patient conditions would establish ground truth. The "ground truth" for the performance evaluation of the new device is the measurement obtained from the legally marketed predicate device.
4. Adjudication Method for the Test Set
Not applicable. As described above, this is a method comparison study. There is no expert adjudication of clinical outcomes or images. The comparison is between quantitative measurements from two different analytical methods.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study
No. This is not an MRMC study. The device is an in vitro diagnostic assay that produces a quantitative result (NT-proBNP concentration), not an imaging device or clinical assessment tool that relies on human reader interpretation. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply.
6. Standalone Performance Study
Yes, a standalone performance study of the revised algorithm (TestPak) was done. The entire "Method Performance Summary" section details the analytical performance of the new device, comparing it directly to the predicate device and assessing its own characteristics (e.g., sensitivity, specificity, interferences, hook effect).
7. Type of Ground Truth Used
The "ground truth" for these studies is the quantitative measurement provided by the legally marketed predicate device (Dade Behring Stratus® CS Acute Care™ pBNP immunoassay K043476/K060548). For the lithium heparin versus sodium heparin comparison, the ground truth is the measurement from the other heparinized sample type. The intent is to show that the new device produces results comparable to the established device/reference.
8. Sample Size for the Training Set
The document does not specify a separate "training set" in the context of machine learning. This device is an immunoassay, not an AI/ML algorithm that requires a distinct training phase on a large dataset for model development. The development of the monoclonal antibody and assay reagents would involve internal R&D processes and optimization, but not in the sense of an "AI training set."
9. How the Ground Truth for the Training Set Was Established
Not applicable. As noted above, this is an immunoassay, not an AI/ML device that uses a "training set" with established ground truth in the typical machine learning sense. The assay's chemical and biological components are developed and validated through laboratory procedures, not by training on a labeled dataset.
{0}------------------------------------------------
AUG 1 7 2007
510(k) Summary
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: | June 30, 2007 |
| Name of Product(s): | Stratus® CS Acute Care™ NT-proBNP (pBNP) TestPak |
| FDA Classification Name(s): | B-type natriuretic peptide test system |
| 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):TestPak | Dade Behring Stratus® CS Acute Care™ NT-proBNP (pBNP)(K043476/K060548) |
Device Description(s):
Method
The Stratus® CS Acute Care™ NT-proBNP method is a two-site sandwich assay based upon solid phase Radial Partition Immunoassav (RPIA) technology. In this procedure, dendrimer linked monoclonal antibody is added to the center portion of a square piece of glass fiber paper in the pBNP TestPak. This antibody recognizes a distinct antigenic site on the NT-proBNP molecule. Sample is then added onto the paper where it reacts with the immobilized antibody. After a short incubation, a conjugate consisting of enzyme-labeled monoclonal antibody directed against a second distinct antigenic site on the NT-proBNP molecule is pipetted onto the reaction zone of the paper. During this second incubation period, enzyme-labeled antibody reacts with the bound NT-proBNP, forming an antibody-antigen-labeled antibody sandwich. The unbound labeled antibody is later eluted from the field of view of the Stratus® CS analyzer by applying a substrate wash solution to the center of the reaction zone. By including substrate for the enzyme within the wash solution, initiation of enzyme activity occurs simultaneously with the wash. The enzymatic rate of the bound fraction increases directly with the concentration of NT-proBNP in the sample. The reaction rate can then be measured by an optical system that monitors the reaction rate via front surface fluorescence: All data analysis functions are performed by the microprocessor within the analyzer.
Intended Use:
Method
The Stratus® CS Acute Care™ NT-proBNP method (pBNP) is an in vitro diagnostic test for the quantitative measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) in heparanized plasma. In individuals suspected of having congestive heart failure (CHF),
{1}------------------------------------------------
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.
Comparison to Predicate Device:
A summary of the features of the revised Dade Behring Stratus® CS Acute Care™ pBNP TestPak and the current (predicate) Dade Behring Stratus® CS Acute Care™ pBNP immunoassay (K043476/K060548) is provided in the following charts.
| Feature | Revised Stratus® CS AcuteCare™ pBNP | Current Stratus® CS pBNP |
|---|---|---|
| Intended Use | For the in vitro quantitativedetermination of N-terminal pro-brain natriuretic peptide in humanplasma as an aid in the diagnosisand assessment of severity ofindividuals suspected of havingcongestive heart failure. The test isfurther indicated for the riskstratification of patients with acutecoronary syndrome and heartfailure. | For the in vitro quantitativedetermination of N-terminal pro-brainnatriuretic peptide in human plasmaas an aid in the diagnosis andassessment of severity of individualssuspected of having congestive heartfailure. The test is further indicatedfor the risk stratification of patientswith acute coronary syndrome andheart failure. |
| Assay Type(detection) | fluorometric immunoassay | fluorometric immunoassay |
| Reportable Range | 15- 20,000 pg/mL | 15- 20,000 pg/mL |
| Antibody | Monoclonal (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 |
| AnalyticalSensitivity | ≤15 pg/mL | ≤15 pg/mL |
| FunctionalSensitivity | ≤ 50 pg/mL | ≤ 50 pg/mL |
{2}------------------------------------------------
| AnalyticalSpecificity | The pharmaceutical Natrecor®shows no significant cross reactivityat 0 and 125 pg/mL NT-proBNP;sixteen other substances also showno significant cross reactivity | The pharmaceutical Natrecor® showsno significant cross reactivity at 0 and125 pg/mL NT-proBNP; sixteen othersubstances also show no significantcross reactivity |
|---|---|---|
| Interferences | No significant interference from:bilirubin, conj. up to 60 mg/dLbilirubin, unconjugated up to 60mg/dL, hemoglobin up to 1000mg/dL, lipemia up to 3000 mg/dL,rheumatoid factors up to 500 IU/mL | No significant interference from:bilirubin, conj. up to 60 mg/dLbilirubin, unconjugated up to 60mg/dL, hemoglobin up to 1000mg/dL, triglycerides up to 3000mg/dL, rheumatoid factors up to 750IU/mL |
| Hook Effect | No high dose effect( up to 833,585 pg/mL) | No high dose effect( up to 1,400,000 pg/mL) |
| Calibration Interval | Calibration curve updated for eachlot, using one level and every 30days, thereafter with the samereagent lot. After calibration updateat completion of each test,recovered values are calculatedfrom stored calibration coefficients. | Calibration curve updated for eachlot, using one level and every 30days, thereafter with the same reagentlot. After calibration update atcompletion of each test, recoveredvalues are calculated from storedcalibration coefficients. |
| Sample Volume | 50 uL | 50 uL |
Method performance Summary:
Analytical Results
Method Comparison
A split sample method comparison demonstrated good agreement between the revised Dade Behring Stratus® CS Acute Care™ NT-proBNP (pBNP) TestPak method and the current (predicate) Dade Behring pBNP TestPak method with heparinized plasma patient samples.
| Comparative | Intercept | Correlation | ||
|---|---|---|---|---|
| Method | Slope | (pg/mL) | Coefficient | n |
| Dade Behring pBNP | 1.02 | 8.2 | 0.99 | 148 |
The model equation for Passing-Bablok linear regression statistics is: [results for revised Stratus CS pBNP] = slope x [comparative method results] + intercept. The range of NT-proBNP values for the monoclonal method in the correlation study was: 15.8 - 18914.2 pg/mL.
Lithium Heparin versus Sodium Heparin
Comparison of lithium heparin versus sodium heparin samples on the Stratus® CS system showed very good agreement. Fifty-one samples were tested in duplicate. The lithium heparin values ranged from
{3}------------------------------------------------
31.2 to 16, 445 pg/mL and sodium heparin values from 32.2 to 17,769 pg/mL. A linear regression gave a slope of 1.06, an intercept of -75 pg /mL and a correlation coefficient of 0.997.
Comments on Substantial Equivalence:
Both the revised Stratus® CS Acute Care™ NT-proBNP (pBNP) TestPak and the current Dade Behring pBNP immunoassays are intended for the quantitative determination of NT-proBNP. Comparative data for human plasma samples demonstrate good analytical agreement between the methods.
Conclusion:
The revised Dade Behring ® CS Acute Care™ NT-proBNP (pBNP) TestPak and the current (predicate) Dade Behring pBNP immunoassays (K043476/K060548) are substantially equivalent based on their intended use and performance characteristics as described above.
George M. Plummer Regulatory Affairs and Compliance Manager June 30, 2007
{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 text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an abstract image of an eagle with its wings spread.
Public Health Service
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Dade Behring Inc. c/o Mr. George M. Plummer Regulatory Affairs & Compliance Manager Bldg. 400, M.S. 514 P.O. Box 6101 Newark, DE 19714-6101
Re: K071834 Trade/Device Name: Stratus® CS Acute Care™ NT-proBNP (pBNP) TestPak Regulation Number: 21 CFR §862.1117 Regulation Name: B-type Natriuretic Peptide Test System. Regulatory Class: Class II Product Code: NBC
Dated: June 30, 2007 Received: July 03, 2007
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. Ilsting of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
AUG 17 2007
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 1egally 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 (240) 276-0490. 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 (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours,
Jean M. Cooper, M.S., D.V.M.
Yean M. Cooper, M.S., 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
{6}------------------------------------------------
INDICATIONS FOR USE STATEMENT
510(k) Number (If Known): k 071834
Device(s) Name(s):
Stratus® CS Acute Care™ NT-proBNP (pBNP) TestPak
Indications for Use:
The Stratus® CS Acute Care™ NT-proBNP method (pBNP) 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 NTproBNP 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. This method is for use by trained health care professionals on the Stratus® CS Stat Fluorometric Analyzer in the clinical laboratory and point of care (POC) settings.
Prescription Use X (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 In Vitro Diagnostic Devices (OIVD)
Carol Benson
Division Sign-Off
Office of In Vitro Diagnostic D Evaluation and Safe
§ 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.”