ELECSYS PROBNP IMMUNOASSAY

K032646 · Roche Diagnostics Corp. · NBC · Nov 12, 2003 · Clinical Chemistry

Device Facts

• Record ID: K032646
• Device Name: ELECSYS PROBNP IMMUNOASSAY
• Applicant: Roche Diagnostics Corp.
• Product Code: NBC · Clinical Chemistry
• Decision Date: Nov 12, 2003
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1117
• Device Class: Class 2

Intended Use

For the in vitro quantitative determination of N-terminal proBrain natriuretic peptide in human serum and plasma. Elecsys proBNP is used as an aid in the diagnosis of individuals suspected of having congestive heart failure. The test is further indicated for the risk stratification of patients with acute coronary syndrome and congestive heart failure. The electrochemiluminescence immunoassay "ECLIA" is intended for use on the Roche Elecsys 1010, Elecsys 2010, and Modular Analytics E170.

Device Story

Elecsys proBNP is an in vitro diagnostic immunoassay for quantitative measurement of NT-proBNP in human serum or plasma. It utilizes an electrochemiluminescence immunoassay (ECLIA) sandwich principle. Input samples are incubated with biotinylated polyclonal anti-NT-proBNP antibodies and ruthenium-labeled polyclonal anti-NT-proBNP antibodies. The resulting sandwich complex binds to streptavidin-coated microparticles. These microparticles are magnetically captured on an electrode surface within the Roche Elecsys 1010, 2010, or Modular Analytics E170 instruments. Application of voltage induces chemiluminescent emission, measured by a photomultiplier. Results are calculated via a calibration curve generated by a 2-point calibration and a master curve provided by reagent barcodes. The output provides quantitative NT-proBNP concentrations, aiding clinicians in diagnosing congestive heart failure and performing risk stratification for acute coronary syndrome and heart failure patients.

Clinical Evidence

Clinical evidence includes previously established analytical performance (precision, linearity, sensitivity, specificity) from K022516. Clinical sensitivity and specificity were previously established across age and gender cohorts. Additional clinical support for the new indication (risk stratification for acute coronary syndrome and congestive heart failure) is provided by three peer-reviewed literature references (James et al., 2003; Jernberg et al., 2002; Fisher et al., 2003) demonstrating the prognostic utility of the Elecsys proBNP assay.

Technological Characteristics

Electrochemiluminescence immunoassay (ECLIA). Analyte: NT-proBNP. Sample: serum/plasma. Calibration: Elecsys proBNP CalSet. Controls: Elecsys PreciControl proBNP/Cardiac. Analyzers: Elecsys 1010, 2010, MODULAR ANALYTICS E170. Traceability: purified synthetic NTG-proBNP (1-76) in human serum matrix.

Indications for Use

Indicated for individuals suspected of having congestive heart failure (CHF) as a diagnostic aid, and for risk stratification of patients with acute coronary syndrome (ACS) and CHF.

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

• Roche Elecsys proBNP (K022516)
• Triage BNP test (K021317)

Submission Summary (Full Text)

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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION SUMMARY
DEVICE ONLY TEMPLATE

A. 510(k) Number:
K032646

B. Analyte:
B-type natriuretic peptide test system (BNP)

C. Type of Test:
Quantitative

D. Applicant:
Roche Diagnostics

E. Proprietary and Established Names:
Elecsys® proBNP assay

F. Regulatory Information:
1. Regulation section:
862.1117 B-type natriuretic peptide test system
2. Classification:
Class II
3. Product Code:
NBC
4. Panel:
75

G. Intended Use:
1. Indication(s) for use:
For the in vitro quantitative determination of N-terminal proBrain natriuretic peptide in human serum and plasma. Elecsys proBNP is used as an aid in the diagnosis of individuals suspected of having congestive heart failure. The test is further indicated for the risk stratification of patients with acute coronary syndrome and congestive heart failure. The electrochemiluminescence immunoassay "ECLIA" is intended for use on the Roche Elecsys 1010, Elecsys 2010, and Modular Analytics E170.
2. Special condition for use statement(s):
3. Special instrument Requirements:

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# H. Device Description:

The Elecsys® proBNP reagent kit is supplied as a 100 test kit. The kit contains the following:

M Streptavidin-coated microparticles, 1 bottle, 6.5 ml: streptavidin-coated microparticles, 0.72mg/ml; binding capacity: 470 ng biotin/mg microparticles; preservative
R1 Anti-NT proBNP-AB-biotin, 1 bottle, 9ml: Biotinylated polyclonal anti-NT-proBNP antibody (sheep) 1.5 μg/ml; phosphate buffer 40 mmol/l, pH 7.4; preservative
R2 Anti-NT-proBNP-Ab-Ru(bpy), 1 bottle, 9ml: polyclonal anti-NT-proBNP antibody (sheep) labeled with ruthenium complex 1.7 μg/ml; phosphate buffer 40 mmol/l, pH 7.4; preservative

# I. Substantial Equivalence Information:

1. Predicate device name(s): Roche Diagnostics Elecsys® proBNP assay
2. Predicate K number(s): K022516
3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | K032646 | K022516 |
| Test principle | Same as K022516 | Electrochemiluminescent assay |
| Sample type | Same as K022516 | Serum and plasma |
| Measuring range | Same as K022516 | 5-35,000 pg/ml |
| Instrument | Same as K022516 | Roche Elecsys 1010, Elecsys 2010, and Modular Analytics E170 |
| Cut-off | Same as K022516 | 125 pg/ml for patients younger than 75 years and 450 pg/ml for patients 75 years and older |
| Differences | | |
| Item | K032646 | K022516 |
| Indications for Use | For the in vitro quantitative determination of N-terminal proBrain natriuretic peptide in human serum and plasma. Elecsys proBNP is used as an aid in the diagnosis of individuals suspected of having congestive heart failure. | For the in vitro quantitative determination of N-terminal proBrain natriuretic peptide in human serum and plasma. Elecsys proBNP is used as an aid in the diagnosis of individuals suspected of having congestive heart failure. |

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| | The test is further indicated for the risk stratification of patients with acute coronary syndrome and congestive heart failure. | |
| --- | --- | --- |

## J. Standard/Guidance Document Referenced (if applicable):

NCCLS EP-5A, Class II Special Control Guidance Document for B-Type Natriuretic Peptide Pre-Market Notifications; Final Guidance for Industry and FDA Reviewers

## K. Test Principle:

The Elecsys® proBNP Test System is an electrochemiluminescence immunoassay (ECLIA). The test uses the sandwich principle. In the first incubation, antibody from the sample, biotinylated polyclonal NT-proBNP-specific antibody and polyclonal NT-proBNP-specific antibody labeled with a ruthenium complex form a sandwich complex. In the second incubation, after addition of streptavidin labeled microparticles, the complex produced is bound to the solid phase via biotin-streptavidin interaction. The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier. Results are determined via a calibration curve. This curve is instrument-specifically generated by a 2-point calibration and a master curve provided via the reagent barcode.

## L. Performance Characteristics (if/when applicable):

### 1. Analytical performance:

a. **Precision/Reproducibility:**
Previously established for K022516. Reproducibility was determined using Elecsys reagents, pooled human sera and controls in a modified protocol (NCCLS EP-5A). Samples were run 6 times daily for 10 days (n = 60) for the 1010 and 2010. For the E170, n = 21. Within run precision (% CV) ranged from 0.9 to 3.0 %, with total precision from 2.2 to 5.8 %.

b. **Linearity/assay reportable range:**
Previously established for K022516. Assay is linear up to 35,000 pg/ml.

c. **Traceability (controls, calibrators, or method):**
Reference standard is purified synthetic NTG-proBNP (1-76) in human serum matrix.

d. **Detection limit:**
Previously established for K022516. Analytical sensitivity (lower detection limit) is 5 pg/ml. Functional sensitivity (the lowest NT-

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proBNP concentration that can be reproducibly measured with a between-run coefficient of variation of 20 %) is < 50 pg/ml.

e. Analytical specificity:
Previously established for K022516. No significant interference was seen from bilirubin up to 35 mg/dL, hemoglobin up to 1.4 g/dL, triglyceride up to 4000 mg/dL, biotin < 30 ng/ml, and rheumatoid factor up to 1500 IU/ml. In vitro tests were performed on 51 commonly used pharmaceuticals. No interference was found. The pharmaceutical Natrecor® does not show cross reactivity with the Elecsys proBNP assay.

f. Assay cut-off:
Previously established for K022516. 125 pg/ml for patients younger than 75 years and 450 pg/ml for patients 75 years and older.

2. Comparison studies:

a. Method comparison with predicate device:
The only difference between K032646 and the predicate K022516 is the change in the Indications for Use. K032646 and K022516 are identical assays, therefore, no method comparison was performed.

b. Matrix comparison:
Previously established for K022516. Serum and heparinized plasma are the recommended sample types for this assay. The criteria used for acceptability was recovery between 90 - 110 % of the serum value or slope 0.9 - 1.1 + coefficient of correlation > 0.95 + intercept within < ±2 analytical sensitivity. When EDTA plasma is used, the values found are approximately 10 % lower.

3. Clinical studies:

a. Clinical sensitivity:
Previously established for K022516.

Sensitivity and Specificity vs. Age and Gender

| Males | < 45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years | < 75 years |
| --- | --- | --- | --- | --- | --- | --- |
| % Sensitivity | 81.6 | 88.2 | 89.6 | 91.7 | 86.5 | 89.0 |
| 95% confidence interval | 68.0-91.24 | 81.27-93.24 | 84.47-93.42 | 85.58-95.77 | 74.21-94.47 | 85.95-91.58 |
| % specificity | 95.7 | 93.3 | 87.8 | 86.7 | 88.9 | 90.0 |
| 95% confidence interval | 78.05-99.89 | 89.07-96.31 | 82.33-91.99 | 75.59-92.07 | 77.37-95.81 | 87.14-92.32 |
| Prevalence | 0.7 | 1.8 | 6.2 | 6.8 | 9.8 | 1.39 |
| Negative predictive value | 100.0 | 99.8 | 99.2 | 99.3 | 96.8 | 99.8 |
| Females | < 45 years | 45-54 years | 55-64 years | 65-74 years | 75 + years | < 75 years |
| --- | --- | --- | --- | --- | --- | --- |
| % Sensitivity | 86.7 | 90.5 | 89.3 | 94.3 | 81.8 | 90.6 |
| 95% confidence interval | 59.54-98.34 | 69.62-98.83 | 78.12-95.97 | 80.84-99.30 | 64.54-93.02 | 84.08-95.02 |
| % specificity | 84.9 | 85.5 | 79.9 | 57.8 | 87.9 | 76.7 |
| 95% confidence interval | 68.1-94.89 | 80.64-89.53 | 74.52-84.63 | 50.21-65.09 | 77.51-94.62 | 73.47-79.72 |
| Prevalence | 0.5 | 1.3 | 3.4 | 6.6 | 9.7 | 1.16 |
| Negative predictive value | 100.0 | 99.9 | 99.5 | 99.3 | 97.8 | 99.9 |

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b. Clinical specificity:
see clinical sensitivity

c. Other clinical supportive data (when a and b are not applicable):
Three peer reviewed literature references are provided demonstrating clinical support of the additional indications for use for the risk stratification of patients with acute coronary syndrome and congestive heart failure. All three studies measured NT-proBNP using the Elecsys proPNP immunoassay. The studies are:

Reference 1: N-Terminal Pro-Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients with Unstable Coronary Artery Disease, GUSTO IV Substudy, James, S.K. et al, Circulation 2003108: 275-281.

Reference 2: N-Terminal Pro-Brain Natriuretic Peptide on Admission for Early Risk Stratification of Patients with Chest Pain and No ST-Segment Elevation, Jernberg, T. et al. Journal of the American College of Cardiology Vol 40, No. 3, 2002: 437-445.

Reference 3: N-Terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Fisher, C. et al. Heart 2003; 89:879-881.

4. Clinical cut-off:
Previously established for K022516. 125 pg/ml for patients younger than 75 years and 450 pg/ml for patients 75 years and older.

5. Expected values/Reference range:
see clinical cut-off

M. Conclusion:

Based upon a review of the information presented in this PMN, I recommend that this device is substantially equivalent to devices regulated by 21 CFR 862.1117, 75 NBC, B-type natriuretic peptide test system, Class II.