Elecsys proBNP II, Elecsys proBNP II STAT
Device Facts
| Record ID | K210546 |
|---|---|
| Device Name | Elecsys proBNP II, Elecsys proBNP II STAT |
| Applicant | Roche Diagnostics |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Mar 31, 2022 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Indications for Use
Immunoassay for the in vitro quantitative determination of N terminal pro Brain natriuretic peptide in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
Device Story
Quantitative immunoassay for N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma; utilizes electrochemiluminescence immunoassay (ECLIA) technology on cobas e immunoassay analyzers. Input: 15 μL patient sample; biotinylated monoclonal anti-NT-proBNP antibody; ruthenium-labeled monoclonal anti-NT-proBNP antibody. Process: Formation of sandwich complex; capture on streptavidin-coated microparticles via magnetic field; voltage application to electrode induces chemiluminescence measured by photomultiplier. Output: Quantitative NT-proBNP concentration determined via instrument-specific calibration curve. Used in clinical laboratories by trained personnel. Biotin scavenger antibody added to attenuate biotin interference. Results aid clinicians in heart failure diagnosis, risk stratification, and cardiovascular event assessment.
Clinical Evidence
No new clinical diagnostic studies performed; substantial equivalence supported by analytical performance and method comparison studies. Method comparison (N=2414) showed high concordance with predicate devices at established age-dependent cutoffs (125 pg/mL for <75 years; 450 pg/mL for ≥75 years). Total agreement for heart failure diagnosis was 98.6-99.7%. Matrix comparison confirmed performance across serum, Li-heparin plasma, and K2-EDTA plasma.
Technological Characteristics
ECLIA technology; sandwich immunoassay; monoclonal antibodies; biotin-binding antibody for interference neutralization; measuring range 36-35000 pg/mL; compatible with cobas e 411 and cobas e 601 analyzers; quantitative output.
Indications for Use
Indicated for individuals suspected of having heart failure, patients with acute coronary syndrome and heart failure for risk stratification, and patients at risk for heart failure with stable coronary artery disease for assessment of increased risk of cardiovascular events and mortality.
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
Submission Summary (Full Text)
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FDA U.S. FOOD & DRUG ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY ONLY
## I Background Information:
A 510(k) Number
K210546
B Applicant
Roche Diagnostics
C Proprietary and Established Names
Elecsys proBNP II, Elecsys proBNP II STAT
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| NBC | Class II | 21 CFR 862.1117 - B-Type Natriuretic Peptide Test System | CH - Clinical Chemistry |
## II Submission/Device Overview:
A Purpose for Submission:
Modification to previously cleared assays (K072437 and K092649) to attenuate biotin interference
B Measurand:
N-terminal pro-BRAIN natriuretic peptide (NT-proBNP)
C Type of Test:
Quantitative immunoassay
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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K210546 - Page 2 of 18
## III Intended Use/Indications for Use:
### A Intended Use(s):
See Indications for Use below.
### B Indication(s) for Use:
Both the Elecsys proBNP II and Elecsys proBNP II STAT have the following intended use:
Immunoassay for the in vitro quantitative determination of N terminal pro Brain natriuretic peptide in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease.
The electrochemiluminescence immunoassay “ECLIA” is intended for use on cobas e immunoassay analyzers.
### C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
For in vitro Diagnostic Use Only
### D Special Instrument Requirements:
Performance data for this submission were generated using the cobas e 411 immunoassay analyzer (Elecsys proBNP II) and the cobas e 601 immunoassay analyzer (Elecsys proBNP II STAT).
## IV Device/System Characteristics:
### A Device Description:
The Elecsys proBNP II and the Elecsys proBNP II STAT consist of three reagents in separate bottles labeled M, R1, and R2:
M: Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL: Streptavidin-coated microparticles 0.72 mg/mL; preservative.
R1: Anti-NT-proBNP-Ab-biotin (gray cap), 1 bottle, 9 mL: Biotinylated monoclonal anti-NT-proBNP antibody (mouse) 1.1 µg/mL; phosphate buffer 40 mmol/L, pH 5.8; preservative.
R2: Anti-NT-proBNP-Ab-Ru(bpy) (black cap), 1 bottle, 9 mL: Monoclonal anti-NT-proBNP antibody (sheep) labeled with ruthenium complex 1.1 µg/mL; Biotin scavenger antibody 1.5 mg/mL; phosphate buffer 40 mmol/L, pH 5.8; preservative.
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K210546 - Page 3 of 18
# B Principle of Operation:
The Elecsys proBNP II assay follows the procedure below:
$1^{\mathrm{st}}$ incubation: Antigen in the sample (15 μL), a biotinylated monoclonal NT-proBNP-specific antibody, and a monoclonal NT-proBNP-specific antibody labeled with a ruthenium complex (Tris(2,2'-bipyridyl)ruthenium(II)-complex $(\mathsf{Ru}(\mathsf{bpy})_3^{2+})$) to form a sandwich complex.
$2^{\mathrm{nd}}$ incubation: After addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase via interaction of biotin and streptavidin.
The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell/ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.
Results are determined via a calibration curve which is instrument specifically generated by 2-point calibration and a master curve provided via the reagent barcode or e-barcode.
The Elecsys proBNP II STAT assay follows a similar procedure outlined above except that the first and second incubations are combined into a single step.
# V Substantial Equivalence Information:
A Predicate Device Name(s):
Elecsys proBNP II, Elecsys proBNP II STAT Immunoassay
B Predicate 510(k) Number(s):
K072437, K092649
C Comparison with Predicate(s):
| Device & Predicate Device(s): | K210546 | K072437 |
| --- | --- | --- |
| Device Trade Name | Elecsys proBNP II | Elecsys proBNP II |
| General Device Characteristic Similarities | | |
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K210546 - Page 4 of 18
| Device & Predicate Device(s): | K210546 | K072437 |
| --- | --- | --- |
| Intended Use/Indications For Use | Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NTproBNP) in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease. | Same |
| Principale of Operation | ECLIA | Same |
| Cutoffs | 125 pg/mL for patients younger than 75 years and 450 pg/mL for patients 75 years or older. | Same |
| General Device Characteristic Differences | | |
| Specimen Types | Serum, Li-heparin plasma, and K_{2}-EDTA plasma | Serum, Li-heparin plasma, K_{2}-EDTA plasma and K_{3}-EDTA plasma |
| Measuring Range | 36-35,000 pg/mL | 5-35,000 pg/mL |
| Reagents | Contains biotin scavenger antibody | Does not contain biotin scavenger antibody |
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K210546 - Page 5 of 18
| Device & Predicate Device(s): | K210546 | K092649 |
| --- | --- | --- |
| Device Trade Name | Elecsys proBNP II STAT | Elecsys proBNP II STAT |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NTproBNP) in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease. | Same |
| Principale of Operation | ECLIA | Same |
| Cutoffs | 125 pg/mL for patients younger than 75 years and 450 pg/mL for patients 75 years or older. | Same |
| General Device Characteristic Differences | | |
| Specimen Types | Serum, Li-heparin plasma, and K_{2}-EDTA plasma | Serum, Li-heparin plasma, K_{2}-EDTA plasma and K_{3}-EDTA plasma |
| Measuring Range | 36-35,000 pg/mL | 5-35,000 pg/mL |
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| Device & Predicate Device(s): | K210546 | K092649 |
| --- | --- | --- |
| Reagents | Contains biotin scavenger antibody | Does not contain biotin scavenger antibody |
VI Standards/Guidance Documents Referenced:
- Clinical and Laboratory Standards Institute (CLSI) EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition
- CLSI EP06-Ed2 Evaluation of the Linearity of Quantitative Measurement Procedures, Approved Guideline—Second Edition
- CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline—Second Edition
- Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers. Document issued on: November 30, 2000
VII Performance Characteristics (if/when applicable):
A Analytical Performance:
1. Precision/Reproducibility:
**Single-site Precision Study**
The precision of the Elecsys proBNP II assay was evaluated on one cobas e 411 and Elecsys proBNP II STAT assay was evaluated on one cobas e 601 analyzer at one internal site with three reagent lots over 21 days.
Testing was conducted with nine serum samples and two controls in single determinations in four separate aliquots (divided into two runs per day) for 21 operating days (n=84). Repeatability, Between-Run, Between-Day, and Within-Laboratory Precision were calculated per recommendations in the CLSI EP05-A3 guideline.
Human serum samples 1, 2, 3, 4, 5, and 8 are pooled unaltered human serum samples. Samples 6 and 7 are human serum sample pools spiked with synthetic NT-proBNP peptide. In addition, 2 control samples were tested, PreciControl Cardiac II 1 and PreciControl Cardiac II 2. The tables below present data from one representative lot of the Elecsys proBNP II and Elecsys proBNP II STAT.
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| Elecsys proBNP II on the cobas e 411 analyzer | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Repeatability | | Between-Run | | Between-Day | | Within Laboratory | |
| Sample | Mean pg/mL | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % |
| Human serum 1 | 55.9 | 2.62 | 4.7 | 1.19 | 2.1 | 3.26 | 5.8 | 4.35 | 7.8 |
| Human serum 2 | 129 | 3.07 | 2.4 | 0.00 | 0.00 | 6.73 | 5.2 | 7.40 | 5.7 |
| Human serum 3 | 423 | 8.91 | 2.1 | 8.51 | 2.0 | 13.2 | 3.1 | 18.0 | 4.3 |
| Human serum 4 | 925 | 23.0 | 2.5 | 11.3 | 1.2 | 36.1 | 3.9 | 44.3 | 4.8 |
| Human serum 5 | 1,924 | 43.8 | 2.3 | 39.3 | 2.0 | 66.5 | 3.5 | 88.8 | 4.6 |
| Human serum 6 | 15,620 | 248 | 1.6 | 272 | 1.7 | 550 | 3.5 | 662 | 4.2 |
| Human serum 7 | 33,526 | 778 | 2.3 | 446 | 1.3 | 1,314 | 3.9 | 1,591 | 4.7 |
| Human serum 8 | 337 | 5.11 | 1.5 | 4.64 | 1.4 | 9.08 | 2.7 | 11.4 | 3.4 |
| PreciControl Cardiac II 1 | 132 | 3.29 | 2.5 | 2.17 | 1.6 | 4.48 | 3.4 | 5.97 | 4.5 |
| PreciControl Cardiac II 2 | 4,477 | 135 | 3.0 | 0.00 | 0.00 | 169 | 3.8 | 216 | 4.8 |
| Elecsys proBNP II STAT on the cobas e 601 analyzer | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Repeatability | | Between-Run | | Between-Day | | Within-Laboratory | |
| Sample (Serum) | Mean pg/mL | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % |
| Human serum 1 | 63.9 | 2.42 | 3.8 | 3.00 | 4.7 | 2.09 | 3.3 | 4.39 | 6.9 |
| Human serum 2 | 144 | 3.36 | 2.3 | 3.29 | 2.3 | 3.51 | 2.4 | 5.87 | 4.1 |
| Human serum 3 | 482 | 12.7 | 2.6 | 4.44 | 0.9 | 12.7 | 2.6 | 18.5 | 3.8 |
| Human serum 4 | 1,060 | 24.6 | 2.3 | 12.5 | 1.2 | 20.4 | 1.9 | 34.4 | 3.2 |
| Human serum 5 | 2,219 | 51.4 | 2.3 | 10.7 | 0.5 | 56.6 | 2.5 | 77.2 | 3.5 |
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| Elecsys proBNP II STAT on the cobas e 601 analyzer | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Repeatability | | Between-Run | | Between-Day | | Within-Laboratory | |
| Human serum 6 | 18,371 | 405 | 2.2 | 188 | 1.0 | 478 | 2.6 | 654 | 3.6 |
| Human serum 7 | 33,967 | 912 | 2.7 | 450 | 1.3 | 869 | 2.6 | 1,338 | 3.9 |
| Human serum 8 | 331 | 5.01 | 1.5 | 5.31 | 1.6 | 10.4 | 3.1 | 12.7 | 3.8 |
| PreciControl Cardiac II 1 | 155 | 4.06 | 2.6 | 2.77 | 1.8 | 3.58 | 2.3 | 6.08 | 3.9 |
| PreciControl Cardiac II 2 | 5,660 | 116 | 2.1 | 71.3 | 1.3 | 138 | 2.4 | 194 | 3.4 |
## Multi-site Precision Study
Inter-instrument variability testing was performed using the Elecsys proBNP II and proBNP II STAT assays on three cobas e 411 analyzers and on three cobas e 601 analyzers, respectively, per recommendations in the CLSI EP5-A3 guideline. One reagent lot for the Elecsys proBNP II and Elecsys proBNP II STAT was used for measurements taken at three laboratory sites, over 5 days with 5 replicates of each sample tested per day.
Human serum (HS) samples 1, 2, 3, 4, 5, and 8 are pooled unaltered human serum samples. Samples 6 and 7 are human serum sample pools spiked with synthetic NT-proBNP peptide. In addition, 2 control samples were tested, PreciControl Cardiac II 1 and PreciControl Cardiac II 2 (referred to as PC 1 and PC 2, respectively, in the tables below).
| cobas e 411 analyzer, Elecsys proBNP II | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Repeatability | | Between-Day | | Between-Site | | Reproducibility | |
| Sample | Mean pg/mL | N | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % |
| HS 1 | 55.2 | 75 | 1.88 | 3.4 | 1.92 | 3.5 | 1.02 | 1.8 | 2.87 | 5.2 |
| HS 2 | 131 | 75 | 2.56 | 1.9 | 2.49 | 1.9 | 3.46 | 2.6 | 4.97 | 3.8 |
| HS 3 | 332 | 75 | 7.41 | 2.2 | 8.15 | 2.5 | 5.5 | 1.7 | 12.3 | 3.7 |
| HS 4 | 471 | 75 | 8.14 | 1.7 | 10.3 | 2.2 | 10.3 | 2.2 | 16.7 | 3.5 |
| HS 5 | 963 | 75 | 20.7 | 2.1 | 26.8 | 2.8 | 13.2 | 1.4 | 36.3 | 3.8 |
| HS 6 | 1,773 | 75 | 38.0 | 2.1 | 39.8 | 2.2 | 20.0 | 1.1 | 58.5 | 3.3 |
| HS 7 | 18,719 | 75 | 311 | 1.7 | 440 | 2.4 | 0.00 | 0.00 | 539 | 2.9 |
| HS 8 | 31,425 | 75 | 735 | 2.3 | 815 | 2.6 | 0.00 | 0.00 | 1,097 | 3.5 |
| PC 1 | 144 | 75 | 2.57 | 1.8 | 3.62 | 2.5 | 1.89 | 1.3 | 4.82 | 3.3 |
| PC 2 | 4,799 | 75 | 97.0 | 2.0 | 79.1 | 1.6 | 0.00 | 0.00 | 125 | 2.6 |
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| cobas e 601 analyzer, Elecsys proBNP II STAT | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Repeatability | | Between-Day | | Between-Site | | Reproducibility | | |
| Sample | Mean pg/mL | N | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % | SD pg/mL | CV % | |
| HS 1 | 52.1 | 75 | 1.25 | 2.4 | 1.74 | 3.3 | 3.91 | 7.5 | 4.46 | 8.6 | |
| HS 2 | 128 | 75 | 2.33 | 1.8 | 3.89 | 3.0 | 9.22 | 7.2 | 10.3 | 8.0 | |
| HS 3 | 317 | 75 | 6.76 | 2.1 | 5.63 | 1.8 | 23.8 | 7.5 | 25.4 | 8.0 | |
| HS 4 | 465 | 75 | 8.50 | 1.8 | 9.74 | 2.1 | 34.6 | 7.4 | 36.9 | 7.9 | |
| HS 5 | 961 | 75 | 16.1 | 1.7 | 23.9 | 2.5 | 74.3 | 7.7 | 79.7 | 8.3 | |
| HS 6 | 1,845 | 75 | 33.7 | 1.8 | 43.0 | 2.3 | 134 | 7.3 | 145 | 7.8 | |
| HS 7 | 18,477 | 75 | 313 | 1.7 | 384 | 2.1 | 1,466 | 7.9 | 1,548 | 8.4 | |
| HS 8 | 30,089 | 75 | 539 | 1.8 | 648 | 2.2 | 2,394 | 8.0 | 2,538 | 8.4 | |
| PC 1 | 145 | 75 | 2.65 | 1.8 | 4.29 | 3.0 | 10.9 | 7.5 | 12.0 | 8.2 | |
| PC 2 | 5,328 | 75 | 91.9 | 1.7 | 114 | 2.1 | 399 | 7.5 | 425 | 8.0 | |
2. Linearity:
One high analyte human, native serum sample with a NT-proBNP concentration above the measuring rage was diluted with analyte free serum. A total of 11 concentrations were prepared that spanned the measuring range. Samples were assayed in 3-fold determination within a single run. Samples were tested using the Elecsys proBNP II on the cobas e 411 and the Elecsys proBNP II STAT on the cobas e 601. The linearity data were analyzed per the recommendations in CLSI EP06-Ed2.
The maximum deviation from linearity observed within the claimed measuring range for the Elecsys proBNP II was -10.5%.
The maximum deviation from linearity observed within the claimed measuring range for the Elecsys proBNP II STAT was -16.9%.
The results of the linearity study support that the Elecsys proBNP II and the Elecsys proBNP II STAT are linear across the claimed measuring range of 36 pg/mL to 35000 pg/mL.
3. Analytical Specificity/Interference:
Endogenous Compounds, Biotin, and Intralipid
The Elecsys proBNP II and Elecsys proBNP II STAT were evaluated for potential interference from endogenous compounds, intralipid, and biotin. Testing was conducted with three levels of NT-proBNP: low (~125-140 pg/mL), medium (~800-1000 pg/mL), and high (~18000-23000 pg/mL). Samples were measured using the Elecsys proBNP II on the cobas e 411 analyzer and using the Elecsys proBNP II STAT on the cobas e 601 analyzer. Interference was defined as a mean percent recovery of samples containing potential
K210546 - Page 9 of 18
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interferent that exceeds $100 \pm 10\%$ of the control sample.
No interference was observed for the following substances up the concentrations listed below.
| Compound | Concentration |
| --- | --- |
| Conjugated Bilirubin | 66 mg/dL |
| Unconjugated Bilirubin | 66 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Intralipid | 1500 mg/dL |
| Biotin | 5000 ng/mL |
| Rheumatoid factors | 1500 IU/mL |
| Albumin | 7 g/dL |
The sponsor's study supports the claims in the labeling that there is no significant interference in the presence of, $\leq 1000\mathrm{mg / dL}$ hemoglobin, $\leq 1500\mathrm{mg / dL}$ Intralipid, $\leq 1500$ IU/mL rheumatoid factors, and $\leq 7\mathrm{g / dL}$ albumin. Although no significant interference was observed in the presence of unconjugated bilirubin, conjugated bilirubin, and biotin at the concentrations listed in the table above, the sponsor is claiming that there is no significant interference at lower concentrations of these compounds; the sponsor is claiming that there is no significant interference in the presence of $\leq 25\mathrm{mg / dL}$ bilirubin and $\leq 3500\mathrm{ng / mL}$ biotin.
# Cross-Reactivity
The cross-reactivity of the Elecsys proBNP II and Elecsys proBNP II STAT was evaluated with two human native serum samples with low (about $150~\mathrm{pg / mL}$ ) and high (about 2500-3000 pg/mL) NT-proBNP levels. The cross-reactant concentrations tested are the highest concentration that may be expected in the intended use population. Samples were measured using the Elecsys proBNP II on the cobas e 411 analyzer and using the Elecsys proBNP II STAT on the cobas e 601 analyzer. Significant cross-reactivity was defined as a mean percent recovery of samples containing potential cross-reactant that exceeds $100 \pm 10\%$ of the control sample.
Elecsys proBNP II Cross-Reactivity
| Cross-reactant | Concentration of cross-reactant tested | Low NT-proBNP | High NT-proBNP |
| --- | --- | --- | --- |
| | | Recovery with cross- reactant [%] | Recovery with cross-reactant [%] |
| Adrenomedullin | 1.0 ng/mL | 91 | 97 |
| Angiotensin I | 0.6 ng/mL | 99 | 99 |
| Angiotensin II | 0.6 ng/mL | 100 | 98 |
| Angiotensin III | 1.0 ng/mL | 100 | 97 |
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| Cross-reactant | Concentration of cross-reactant tested | Low NT-proBNP | High NT-proBNP |
| --- | --- | --- | --- |
| | | Recovery with cross- reactant [%] | Recovery with cross-reactant [%] |
| Arg-Vasopressin | 1.0 ng/mL | 100 | 100 |
| Endothelin | 20 pg/mL | 100 | 97 |
| Aldosterone | 0.6 ng/mL | 97 | 96 |
| Renin | 50 ng/mL | 94 | 94 |
| BNP32 | 3.5 μg/mL | 100 | 100 |
| CNP22 | 2.2 μg/mL | 91 | 96 |
| Urodilatin | 3.5 μg/mL | 100 | 99 |
| ANP 1-28 | 3.1 μg/mL | 101 | 99 |
| NT-proANP | 3.5 μg/mL | 99 | 96 |
| (1-30) [preproANP (26-55)] | | | |
| NT-proANP (31-67) | 1.0 ng/mL | 97 | 97 |
| [preproANP 56-92] | | | |
| NT-proANP (79-98) | 1.0 ng/mL | 100 | 103 |
| [preproANP 104-123] | | | |
Elecsys proBNP II STAT Cross-Reactivity
| Cross-reactant | Concentration of cross-reactant tested | Low NT-proBNP | High NT-proBNP |
| --- | --- | --- | --- |
| | | Recovery with cross- reactant [%] | Recovery with cross-reactant [%] |
| Adrenomedullin | 1.0 ng/mL | 99 | 101 |
| Angiotensin I | 0.6 ng/mL | 99 | 99 |
| Angiotensin II | 0.6 ng/mL | 100 | 100 |
| Angiotensin III | 1.0 ng/mL | 98 | 96 |
| Arg-Vasopressin | 1.0 ng/mL | 98 | 98 |
| Endothelin | 20 pg/mL | 100 | 99 |
| Aldosterone | 0.6 ng/mL | 98 | 97 |
| Renin | 50 ng/mL | 96 | 94 |
| BNP32 | 3.5 μg/mL | 100 | 98 |
| CNP22 | 2.2 μg/mL | 97 | 96 |
| Urodilatin | 3.5 μg/mL | 99 | 99 |
| ANP 1-28 | 3.1 μg/mL | 100 | 99 |
| NT-proANP(1-30) | 3.5 μg/mL | 96 | 95 |
| [preproANP (26-55)] | | | |
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| Cross-reactant | Concentration of cross-reactant tested | Low NT-proBNP | High NT-proBNP |
| --- | --- | --- | --- |
| | | Recovery with cross- reactant [%] | Recovery with cross-reactant [%] |
| NT-proANP(31-67) | 1.0 ng/mL | 100 | 99 |
| [preproANP 56-92] | | | |
| NT-proANP(79-98) | 1.0 ng/mL | 99 | 106 |
| [preproANP 104-123] | | | |
No significant cross-reactivity to the substances listed in the tables above was observed for the Elecsys proBNP II and the Elecsys proBNP II STAT.
# Exogenous Substances
The Elecsys proBNP II and Elecys proBNP II STAT were evaluated for potential interference from pharmaceutical compounds. Testing was conducted with two levels of native human samples with $\sim 125\mathrm{pg / mL}$ and $\sim 2000\mathrm{pg / mL}$ NT-proBNP. The drugs and drug levels tested were determined per recommendations in CLSI EP07 and CLSI EP37. Samples were measured using the Elecsys proBNP II on the cobas e 411 analyzer and using the Elecsys proBNP II STAT on the cobas e 601 analyzer. Interference was defined as a mean percent recovery of samples containing potential interferent that exceeds $100\pm 10\%$ of the control sample.
No significant interference was observed with the 50 pharmaceutical compounds listed in the table below:
| Common therapeutic drugs | Drug concentration [mg/dL] | Special therapeutic drugs | Drug concentration [mg/dL] |
| --- | --- | --- | --- |
| Acetylcysteine | 15.0 | Carvedilol | 15.0 |
| Ampicillin-Na | 100.0 | Clopidogrel | 7.5 |
| Ascorbic acid | 30.0 | Digoxin | 0.05 |
| Cefoxitin | 250.0 | Epinephrine | 0.037 |
| Heparin | 5000 IU/L | Insulin | 0.084 |
| Levodopa | 2.0 | Lidocaine | 10.0 |
| Methyldopa | 2.0 | Lisinopril | 4.0 |
| Metronidazole | 20.0 | Methylprednisolone | 8.0 |
| Doxycycline | 5.0 | Metoprolol | 1.5 |
| Acetylsalicylic Acid | 100.0 | Nifedipine | 6.0 |
| Rifampicin | 6.0 | Marcumar | 0.6 |
| Cyclosporine | 0.5 | Propafenone | 90.0 |
| Phenylbutazone | 40.0 | Reteplase | 0.112 |
| Acetaminophen | 20.0 | Simvastin | 4.0 |
| Ibuprofen | 50.0 | Spirinolactone | 40.0 |
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| Common therapeutic drugs | Drug concentration [mg/dL] | Special therapeutic drugs | Drug concentration [mg/dL] |
| --- | --- | --- | --- |
| Theophylline | 10.0 | Tolbutamide | 300.0 |
| Ca-Dobesilate | 20.0 | Torasemide | 20.0 |
| | Verapamil | 12.0 | |
| | | Propranolol | 0.032 |
| | | Enalapril | 4.0 |
| | | Captopril | 5.0 |
| | | Gentamycin | 50.0 |
| | | Lovastatin | 8.0 |
| | | Pravastatin | 4.0 |
| | | Bisoprolol | 1.0 |
| | | Glycerol nitrate | 19.2 |
| | | Molsidomin | 2.4 |
| | | Nicardipine | 9.0 |
| | | Streptokinase | 300 IE/mL |
| | | Urokinase | 600 IE/mL |
| | | Digitoxin | 0.03 |
| | | Sotalol | 32.0 |
| | | Low molecular weight heparin | 1.8 |
4. Assay Reportable Range:
36-35,000 pg/mL
5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
The assays are traceable gravimetrically to an in-house reference material. The reference material has not changed compared with clearances of previous generations of these devices.
6. Detection Limit:
Limit of Blank (LoB):
The LoB of the Elecsys proBNP II on the cobas e 411 analyzer and of the Elecsys proBNP II STAT on the cobas e 601 analyzer was determined per recommendations in CLSI EP17-A2. In total, 60 determinations of an analyte-free sample were obtained on one instrument in 6 runs with 10-fold determination per run. Three lots of reagent were used in the experimental design. The LoB was determined as the 95th percentile of measurements of blank samples.
The sponsor's study supports that the LoB for the Elecsys proBNP II and the Elecsys proBNP II STAT is ≤ 8 pg/mL.
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Limit of Detection (LoD):
The LoD of the Elecsys proBNP II on the cobas e 411 analyzer and of Elecsys proBNP II STAT (updated assay) on the cobas e 601 analyzer was determined per recommendations in CLSI EP17-A2. Five low-level human serum samples were measured on one instrument in 60 total determinations per sample per reagent lot. The study was conducted using three reagent lots. The LoD was determined by parametric analysis.
The sponsor's study supports the claimed LoD of 10 pg/mL for the Elecsys proBNP II and the Elecsys proBNP II STAT.
Limit of Quantitation (LoQ):
The LoQ of the Elecsys proBNP II on the cobas e 411 analyzer and of the Elecsys proBNP II STAT on the cobas e 601 analyzer was determined per recommendations in CLSI EP17-A2. Nine native, unaltered serum samples were tested with the Elecsys proBNP II and 10 native, unaltered serum samples were tested with the Elecsys proBNP II STAT. Each sample was tested in 5 replicates on one instrument in singleton per day, over 5 days with 1 run per day. Three lots of reagent were used in the study. A total of n=25 measured values were obtained for each sample. The LoQ was determined as the lowest concentration of analyte which can be measured with an intermediate precision of 20% CV.
The sponsor's study supports the claimed LoQ of 36 pg/mL for the Elecsys proBNP II and the Elecsys proBNP II STAT.
7. Assay Cut-Off:
Previously established in K022516
B Comparison Studies:
1. Method Comparison with Predicate Device:
a) Elecsys proBNP II
The sponsor obtained 2414 native serum samples each collected from independent subjects in the sponsor's intended use population from the US and Europe. The sponsor conducted a Passing-Bablok regression analysis on 1940 native serum samples comparing the measurements made using the biotin-remediated Elecsys proBNP II (subject device, y) with measurements made using the non-biotin remediated Elecsys proBNP II (predicate device, x). A total of 474 samples were not included in the regression analysis because the NT-proBNP values fell outside the common measuring range of the predicate and subject devices. The following Passing-Bablok regression fit was determined from the comparison study:
$$
y = 0.98x - 2.88
$$
The 95% confidence interval (CI) for the estimate of the slope was between 0.98 and 0.98 and the 95% CI for the estimate of the intercept was between -3.20 and -2.46.
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Based on the regression analysis above, the sponsor will include in the labeling the following information concerning the predicted systematic differences between the biotin-remediated Elecsys proBNP II and non-biotin-remediated Elecsys proBNP II assays at different NT-proBNP concentrations:
| | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | | | | |
| | | (-4.4,-3.9) | (-3.0,-2.7) | (-2.6,-2.4) | (-2.3,-2.1) | (-2.2,-1.9) |
The sponsor also conducted a concordance analysis with the 2414 native serum samples collected from subjects in the US and Europe comparing the agreement between the subject and predicate devices at the two age-dependent cutoffs (125 pg/mL for patients <75 years of age and 450 pg/mL for patients ≥75 years of age). Of these subjects with a confirmed diagnosis of heart failure (N = 1015), the total agreement between the subject and predicate devices was 98.6% (1001/1015). Of the subjects without a confirmed heart failure diagnosis (N = 1399) the total agreement between the subject and predicate devices was 98.7% (1381/1399). In a subset of US subjects, heart failure severity was classified per the New York Heart Association Functional Classification for heart failure (NYHA Class I-IV). The total agreement between the subject and predicate devices for subjects classified in NYHA Classes I, II, II, and IV were 98% (193/197), 98.7% (224/227), 98.4% (254/258), and 98.2% (166/169), respectively.
## b) Elecsys proBNP II STAT
The sponsor obtained 2414 native serum samples each collected independent subjects in the sponsor's intended use population from the US and Europe. The sponsor conducted a Passing-Bablok regression analysis on 1928 native serum samples comparing the measurements made using the biotin-remediated Elecsys proBNP II STAT (subject device, y) with measurements made using the non-biotin remediated Elecsys proBNP II STAT (predicate device, x). A total of 486 samples were not included in the regression analysis because the NT-proBNP values fell outside the common measuring range of the predicate and subject devices. The following Passing-Bablok regression fit was determined from the comparison study:
$$
y = 1.01x - 1.60
$$
The 95% confidence interval (CI) for the estimate of the slope was between 1.00 and 1.01 and the 95% CI for the estimate of the intercept was between -2.09 and -1.16.
Based on the regression analysis above, the sponsor will include the following information concerning the predicted systematic differences between the biotin-remediated Elecsys proBNP II STAT and non-biotin-remediated Elecsys proBNP II
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STAT assays at different NT-proBNP concentrations in the labeling,
The sponsor also conducted a concordance analysis with the 2414 native serum samples collected from subjects in the US and Europe comparing the agreement between the subject and predicate devices at the two age-dependent cutoffs (125 pg/mL for patients <75 years of age and 450 pg/mL for patients ≥75 years of age). Of these subjects with a confirmed diagnosis of heart failure (N = 1015), the total agreement between the subject and predicate devices was 99.7% (1012/1015). Of the subjects without a confirmed heart failure diagnosis (N = 1399) the total agreement between the subject and predicate devices was 99.2% (1388/1399). In a subset of US subjects, heart failure severity was classified per the New York Heart Association Functional Classification for heart failure (NYHA Class I-IV). The total agreement between the subject and predicate devices for subjects classified in NYHA Classes I, II, II, and IV were 100% (197/197), 99.6% (226/227), 99.6% (257/258), and 99.4% (168/169), respectively.
The sponsor provided information on the potential impact the performance characteristics of the Elecsys proBNP II and the Elecsys proBNP II STAT may have on the labeled clinical performance of the device. This information was reviewed and determined to support that the clinical performance claims are applicable to the Elecsys proBNP II and Elecsys proBNP II STAT.
The sponsor also provided information to support the use of the frozen samples used in the method comparison and concordance studies.
## 2. Matrix Comparison:
The sponsor conducted a matrix comparison study with the Elecsys proBNP II on the cobas e 411 and with the Elecsys proBNP II STAT on the cobas e 601 by comparing values obtained from testing matched native (single donors) serum, lithium heparin (Li-Heparin) plasma, and K2-EDTA plasma samples. The following tables summarize the Passing-Bablok regression analysis comparing the results from serum to those from lithium heparin plasma and K2-EDTA plasma samples.
Sample Matrix Comparison for Elecsys proBNP II
| Elecsys proBNP II | Li-Heparin | K2-EDTA |
| --- | --- | --- |
| Slope
[95% LCL/UCL] | 0.990
[0.981/0.997] | 1.01
[0.994/1.01] |
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| Elecsys proBNP II | Li-Heparin | K2-EDTA |
| --- | --- | --- |
| Intercept (pg/mL)
[95% LCL/UCL] | 0.898
[-0.981/3.45] | -0.985
[-4.23/2.21] |
| Correlation coefficient
Pearson’s r | 0.998 | 0.999 |
| Serum/plasma pairs | 98 | 111 |
Sample Matrix Comparison for Elecsys proBNP II STAT
| Elecsys proBNP II STAT | Li-Heparin | K2-EDTA |
| --- | --- | --- |
| Slope [95% LCL/UCL] | 0.983
[0.974/0.988] | 1.00
[0.991/1.01] |
| Intercept (pg/mL)
[95% LCL/UCL] | 0.803
[-1.09/3.25] | -2.41
[-7.75/0.275] |
| Correlation coefficient
Pearson’s r | 0.998 | 0.999 |
| Serum/plasma pairs | 98 | 112 |
The sponsor's study results support claims for testing serum, lithium heparin, and K2-EDTA plasma with the Elecsys proBNP II on the cobas e 411 and the Elecsys proBNP II STAT on the cobas e 601.
## C Clinical Studies:
1. **Clinical Sensitivity:**
Previously established in K022516
2. **Clinical Specificity:**
Previously established in K022516
3. **Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):**
See section B Comparison Studies, above.
## D Clinical Cut-Off:
Previously established in K022516
## E Expected Values/Reference Range:
Previously established for K022516
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VIII Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.
IX Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
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