DIMENSION NT-PROBNP FLEX REAGENT CARTRIDGE METHOD, DIMENSION PBNP CALIBRATOR, MODELS RF423, RC423
Device Facts
| Record ID | K041417 |
|---|---|
| Device Name | DIMENSION NT-PROBNP FLEX REAGENT CARTRIDGE METHOD, DIMENSION PBNP CALIBRATOR, MODELS RF423, RC423 |
| Applicant | Dade Behring, Inc. |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Jul 20, 2004 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Indications for Use
The PBNP assay used on the Dimension® clinical chemistry system with the heterogenous immunoassay module is an in vitro diagnostic assay for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human plasma. Measurements of NT-proBNP are used as an aid in the diagnosis of individuals suspected of having congestive heart failure (CHF). The PBNP Calibrator is an in vitro diagnostic product intended to be used to calibrate the N-terminal pro-brain natriuretic peptide (NT-proBNP) method for the Dimension® clinical chemistry system with the heterogenous immunoassay module.
Device Story
The Dimension® NT-proBNP Flex® reagent cartridge is an in vitro diagnostic assay for use on the Dimension® clinical chemistry system. It utilizes a one-step sandwich enzyme immunoassay principle. Patient plasma samples are incubated with chromium dioxide particles coated with polyclonal antibodies (recognizing the N-terminal part of proBNP) and an alkaline phosphatase (ALP)-labeled polyclonal antibody. After magnetic separation and washing, the sandwich-bound ALP triggers an amplification cascade: ALP dephosphorylates synthetic flavin adenine dinucleotide phosphate (FADP) to FAD; FAD activates apo D-amino acid oxidase; the resulting holo D-amino acid oxidase produces hydrogen peroxide (H2O2). H2O2, in the presence of horseradish peroxidase, converts DCHBS and 4-AAP into a colored product measured at 510 nm. The color intensity is directly proportional to NT-proBNP concentration. The device is operated by laboratory personnel in a clinical setting. Results assist clinicians in diagnosing CHF. The calibrator is a frozen liquid containing synthetic human NT-proBNP in a bovine albumin matrix used to calibrate the assay.
Clinical Evidence
Clinical study evaluated 308 non-CHF individuals and 227 CHF patients. Sensitivity/specificity calculated using age-stratified cut-offs (125 pg/mL <75 yrs; 450 pg/mL ≥75 yrs). Sensitivity ranged 77-91%; specificity 77-94%. ROC analysis yielded AUC 0.916 (95% CI 0.892-0.939).
Technological Characteristics
One-step enzyme immunoassay; sandwich principle. Reagents in flexible plastic cartridge. Chromium dioxide particles; polyclonal sheep antibodies; ALP conjugate; FADP substrate. Colorimetric detection at 510 nm. Requires Dimension clinical chemistry system. Plasma samples (lithium heparin, sodium heparin, EDTA).
Indications for Use
Indicated for the quantitative determination of NT-proBNP in human plasma to aid in the diagnosis of individuals suspected of having congestive heart failure (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
Related Devices
- K071767 — DIMENSIONS PBNP FLEX REAGENT CARTRIDGE, MODEL RF423A · Dade Behring, Inc. · Aug 4, 2007
- K042347 — MODIFICATION TO DIMENSION NT-PROBNP FLEX REAGENT CARTRIDGE METHOD · Dade Behring, Inc. · Nov 19, 2004
Submission Summary (Full Text)
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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION SUMMARY
DEVICE ONLY TEMPLATE
A. 510(k) Number:
K041417
B. Purpose for Submission:
New device
C. Analyte:
B-type natriuretic peptide test system (BNP)
D. Type of Test:
Quantitative
E. Applicant:
Dade Behring, Inc.
F. Proprietary and Established Names:
Dimension® NT-proBNP (PBNP) Flex® reagent cartridge method
Dimension® PBNP Calibrator
G. Regulatory Information:
1. Regulation section:
21 CFR 862.1117, B-type natriuretic peptide test system
21 CFR 862.1150, Calibrator, secondary
2. Classification:
Class II
3. Product Code:
NBC
JIT
4. Panel:
75
H. Intended Use:
1. Intended use(s):
The PBNP assay used on the Dimension® clinical chemistry system with the heterogenous immunoassay module is an in vitro diagnostic assay for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human plasma. Measurements of NT-proBNP are used as an aid in the diagnosis of individuals suspected of having congestive heart failure (CHF).
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The PBNP Calibrator is an *in vitro* diagnostic product intended to be used to calibrate the N-terminal pro-brain natriuretic peptide (NT-proBNP) method for the Dimension® clinical chemistry system with the heterogenous immunoassay module.
2. **Indication(s) for use:**
The Dade Behring Dimension® PBNP Flex® reagent cartridge method is an *in vitro* diagnostic assay for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human plasma. Measurements of NT-proBNP are used as an aid in the diagnosis of individuals suspected of having congestive heart failure.
The Dade Behring Dimension® PBNP Calibrator is intended to be used to calibrate the N-terminal pro-brain natriuretic peptide (PBNP) method for the Dade Behring Dimension® clinical chemistry system.
3. **Special condition for use statement(s):**
Prescription use
4. **Special instrument Requirements:**
Dade Behring Dimension RxL Max™, RxL, and Xpand®
I. **Device Description:**
The Dade Behring Dimension® PBNP Flex® reagent cartridge method is an *in vitro* diagnostic test that consists of prepackaged reagents in a flexible plastic cartridge for use only on the Dimension® clinical chemistry system. The Dade Behring PBNP calibrator is a frozen liquid product containing synthetic human NT-proBNP in a bovine albumin matrix with stabilizers and preservative. The calibrator kit consists of 10 vials, 2 vials at each of 5 levels, with 1.0 mL in each vial.
J. **Substantial Equivalence Information:**
1. **Predicate device name(s):**
Roche Diagnostics Elecsys® proBNP Immunoassay
2. **Predicate K number(s):**
K022516
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3. Comparison with predicate:
| Similarities | | |
| --- | --- | --- |
| Item | Dimension NT-proBNP | Roche NT-proBNP |
| Assay type | Immunoassay | Immunoassay |
| Antibody | Polyclonal sheep antibody | Polyclonal sheep antibody |
| Cut-off | 125 pg/mL for patients <75 years | 125 pg/mL for patients <75 years |
| | 450 pg/mL for patients ≥ 75 years | 450 pg/mL for patients ≥ 75 years |
| Reference | Roche purified synthetic NT-proBNP | Roche purified synthetic NT-proBNP |
| Differences | | |
| Item | Dimension NT-proBNP | Roche NT-proBNP |
| Indications for Use | in vitro diagnostic assay for the quantitative measurement of NT-proBNP in human plasma. Measurements of NT-proBNP are used as an aid in the diagnosis of individuals suspected of having congestive heart failure | in vitro quantitative determination of NT-proBNP in human serum and plasma 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. |
| Reportable range | 10-30,000 pg/mL | 5-35,000 pg/mL |
| Analytical sensitivity | ≤ 10 pg/mL | 5 pg/ml |
| Functional sensitivity | ≤ 30 pg/mL | < 50 pg/mL |
| Sample volume | 50 μL | 20 μL |
K. Standard/Guidance Document Referenced (if applicable):
NCCLS EP 5-A, Class II Special Controls Guidance Document for B-Type Natriuretic Peptide Premarket Notifications: Final Guidance for Industry and FDA Reviewers (11/30/2000)
L. Test Principle:
The PBNP method is a one-step enzyme immunoassay based on the "sandwich" principle. Sample is incubated with chromium dioxide particles coated with polyclonal antibodies which recognize an epitope located in the N-terminal part of proBNP, and a conjugate reagent [alkaline phosphatase (ALP)] labeled polyclonal antibody specific for a second independent epitope on NT-proBNP, to form a particle/NT-proBNP/ conjugate sandwich. Unbound conjugate is removed by magnetic separation and washing. After separation and washing, the conjugate
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sandwich is transferred to the cuvette where the sandwich-bound ALP triggers an amplification cascade. ALP dephosphorylates synthetic flavin adenine dinucleotide phosphate (FADP) to produce FAD. FAD binds to apo D-amino acid oxidase and converts it to active holo D-amino acid oxidase. Each molecule of holo D-amino acid oxidase produces multiple molecules of hydrogen peroxide (H₂O₂). H₂O₂ in the presence of horseradish peroxidase (HRP), converts 3,5-dichloro-2-hydroxybenzenesulfonic acid (DCHBS) and 4-aminoantipyrine(4-AAP) to a colored product that absorbs at 510 nm. The color change measured is directly proportional to the concentration of NT-proBNP present in the patient sample.
## M. Performance Characteristics (if/when applicable):
### 1. Analytical performance:
a. Precision/Reproducibility:
| | | Within-Run Precision | | Total Precision | |
| --- | --- | --- | --- | --- | --- |
| Sample | Mean (pg/mL) | SD (pg/mL) | % CV | SD (pg/mL) | % CV |
| Human plasma pool 1 | 159 | 3.4 | 2.2 | 9.1 | 5.7 |
| Internal QC Pool 1 | 449.5 | 8.1 | 1.8 | 16.6 | 3.7 |
| Internal QC Pool 2 | 956.7 | 15.3 | 1.6 | 34.9 | 3.6 |
| Control Level 1 | 175.5 | 2.0 | 1.1 | 6.8 | 3.8 |
| Control Level 2 | 3733.8 | 71.8 | 1.9 | 115.9 | 3.1 |
Reproducibility testing was done in accordance with NCCLS EP5-A. Specimens at each level were analyzed in duplicate once per day for 20 days.
b. Linearity/assay reportable range:
The reportable range of the assay is from 10-30,000 pg/mL. A high PBNP plasma pool (PBNP = 35979.5 pg/mL) was diluted with a low PBNP pool (PBNP = 6.8 pg/mL) to produce 6 levels of PBNP. High range linearity was evaluated by comparing observed vs. expected values obtained with the PBNP method. A linear regression analysis was then performed on the data to yield the following: slope = 0.954, r=0.999, intercept = 512 pg/mL. Lower range linearity was evaluated by diluting two patient samples (Sample 1 PBNP = 4616 pg/mL, Sample 2 PBNP = 1037 pg/mL) to produce 6 levels of PBNP for each sample. Linear regression analyses were performed on the data to yield the following:
Sample 1: slope = 0.990, r = 1.000, intercept = -8.50
Sample 2: slope = 1.030, r = 0.999, intercept = -1.63
Hook effect was evaluated using samples containing NT-proBNP concentrations ranging from 0 to 300,000 pg/mL. Data indicated no hook effect up to 300,000 pg/mL.
c. Traceability (controls, calibrators, or method):
The assay is referenced to Roche purified synthetic NT-proBNP. The assigned values for the Dimension® PBNP Calibrator are
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referenced to a master pool containing synthetic human N-terminal pro-brain natriuretic peptide.
# d. Detection limit:
The analytical sensitivity for the PBNP assay is $\leq 10\mathrm{pg / mL}$ . This is defined as the concentration at two standard deviations ( $n = 20$ ) of a sample devoid of NT-proBNP. Functional sensitivity was determined by performing a 20 day ANOVA experiment using samples prepared with Roche synthetic antigen and the Dimension® PBNP calibrator base (zero concentration level) targeted at low NT-proBNP concentrations. Total % CV was plotted versus the concentration for each sample. The functional sensitivity was determined to be $\leq 30\mathrm{pg / mL}$ .
# e. Analytical specificity:
No significant interference was found for bilirubin (conjugated) up to $60\mathrm{mg / dL}$ , bilirubin (unconjugated) up to $20\mathrm{mg / dL}$ , hemoglobin up to $1000\mathrm{mg / dL}$ , triglycerides up to $3000\mathrm{mg / dL}$ , and rheumatoid factor up to $500\mathrm{IU / mL}$ . The pharmaceutical Natrecor® shows no significant cross reactivity at 0 and $125\mathrm{pg / mL}$ NT-proBNP. An extensive list of other compounds was evaluated for interference and was found to have no significant interference or cross reactivity. A list of these compounds is present in the PBNP labeling.
# f. Assay cut-off:
The recommended medical decision thresholds by age group are:
Patients $< 75$ years $125\mathrm{pg / mL}$
Patients $\geq 75$ years $450~\mathrm{pg / mL}$
# 2. Comparison studies:
# a. Method comparison with predicate device:
Comparison using split patient heparinized plasma samples between the Dade Behring Dimension® PBNP Flex method and the predicate Roche Elecsys® proBNP method demonstrated the following method comparison using samples with values ranging from 16.1 – 29,893.1 pg/mL:
| Comparative Method | Slope | Intercept (pg/mL) | Correlation Coefficient | n |
| --- | --- | --- | --- | --- |
| Roche Elecsys® proBNP | 0.90 | -15.4 | 0.985 | 352 |
# b. Matrix comparison:
Plasma specimens (lithium heparin, sodium heparin, and EDTA) may be used for the PBNP assay. Serum samples should not be used with the PBNP assay. Lithium heparin samples $(n = 55)$ ranging from 13 to $29,221~\mathrm{pg / mL}$ when compared to sodium heparin and EDTA samples gave slopes of 0.95 and 0.96, correlation coefficients of 0.998 and 0.998, and intercepts of 0.9 and 10.9 respectively using Passing-Bablock regression statistics.
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3. Clinical studies:
a. Clinical sensitivity:
Clinical Studies: For the Reference Study Group, NT-proBNP concentrations were determined in 308 individuals without congestive heart failure (163 women and 145 men). This population included apparently healthy individuals and individuals with diabetes, hypertension, and pulmonary disease. For the Disease Study Group, NT-proBNP concentrations were determined in 227 patients diagnosed with congestive heart failure (CHF). This population included 69 women and 158 men.
The tables below show the clinical sensitivity and specificity of the Dimension® PBNP assay using a cutoff of 125 pg/mL for patients younger than 75 years and 450 pg/mL for patients 75 years or older.
| Males | | |
| --- | --- | --- |
| | <75 yrs | ≥75 yrs |
| % Sensitivity | 84 | 91 |
| 95% Confidence Interval | 77 - 91 | 84 - 99 |
| % Specificity | 94 | 77 |
| 95% Confidence Interval | 90 - 99 | 67 - 88 |
| Females | | |
| --- | --- | --- |
| | <75 yrs | ≥75 yrs |
| % Sensitivity | 77 | 91 |
| 95% Confidence Interval | 64 - 89 | 79 - 100 |
| % Specificity | 93 | 88 |
| 95% Confidence Interval | 89 - 98 | 80 - 96 |
b. Clinical specificity:
See Clinical Sensitivity above
c. Other clinical supportive data (when a and b are not applicable):
4. Clinical cut-off:
The Receiver Operator Curve (ROC) compares the clinical sensitivity and specificity at various cutoffs. The ROC analysis for the Dimension® PBNP assay is shown below. The AUC for the Dimension® PBNP assay is 0.916 with a 95% confidence interval of 0.892 to 0.939.
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A box and whiskers plot of the clinical study population is presented below. Recommended clinical thresholds are $125~\mathrm{pg / mL}$ for patients younger than 75 years and $450~\mathrm{pg / mL}$ for patients 75 years and older. Three disease group samples with values above the assay range are not displayed in the plot.
5. Expected values/Reference range:
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NT-proBNP concentrations in the Reference Group are shown in the following tables. The recommended medical decision thresholds, by age group, are:
Patients $< 75$ years:
125 pg/mL [14.8 pmol/L]
Patients $\geq 75$ years:
450 pg/mL [53.2 pmol/L]
# Reference Study Group
NT-proBNP concentrations were determined in 308 individuals without congestive heart failure (163 women and 145 men). This population included apparently health individuals and individuals with diabetes, hypertension, and pulmonary disease. The statistics for NT-proBNP concentrations in the reference study group are shown in the following table.
| All | | |
| --- | --- | --- |
| | <75 yrs | ≥ 75 yrs |
| Mean | 34.9 | 353.6 |
| SD | 40.7 | 775.8 |
| Median | 19.3 | 125.6 |
| 95thPercentile | 101.7 | 1372.8 |
| % < 125 pg/mL | 96 | - |
| % < 450 pg/mL | - | 83 |
| N | 186 | 122 |
| Males | | |
| --- | --- | --- |
| | <75 yrs | ≥ 75 yrs |
| Mean | 30.9 | 414.3 |
| SD | 42.3 | 889.0 |
| Median | 13.6 | 111.8 |
| 95thPercentile | 114.3 | 1475.7 |
| % < 125 pg/mL | 95 | - |
| % < 450 pg/mL | - | 77 |
| N | 83 | 62 |
| Females | | |
| --- | --- | --- |
| | <75 yrs | ≥ 75 yrs |
| Mean | 38.1 | 291.0 |
| SD | 39.4 | 639.7 |
| Median | 24.5 | 131.3 |
| 95thPercentile | 101.7 | 1080.7 |
| % < 125 pg/mL | 97 | - |
| % < 450 pg/mL | - | 88 |
| N | 103 | 60 |
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# Disease Study Group
Blood samples were obtained from 227 patients diagnosed with congestive heart failure (CHF). The population included 69 women and 158 men. The descriptive statistics and New York Heart Association (NYHA) functional classes are provided below.
| CHF Population - All | | |
| --- | --- | --- |
| | <75 yrs | ≥75 yrs |
| Mean | 3305.9 | 4579.3 |
| SD | 7527.8 | 8721.2 |
| Median | 1033.7 | 2513.4 |
| 95^{th} Percentile | 12127.1 | 11398.6 |
| % > 125 pg/mL | 82 | - |
| % > 450 pg/mL | - | 91 |
| N | 158 | 69 |
| CHF Population - Males | | |
| --- | --- | --- |
| | <75 yrs | ≥75 yrs |
| Mean | 3638.7 | 5773.0 |
| SD | 8557.5 | 10238.5 |
| Median | 1148.2 | 3086.6 |
| 95^{th} Percentile | 12127.1 | 14118.8 |
| % > 125 pg/mL | 84 | - |
| % > 450 pg/mL | - | 92 |
| N | 111 | 47 |
| CHF Population - Females | | |
| --- | --- | --- |
| | <75 yrs | ≥75 yrs |
| Mean | 2520.0 | 2028.9 |
| SD | 4170.8 | 2581.3 |
| Median | 616.0 | 1077.1 |
| 95^{th} Percentile | 10961.2 | 8891.2 |
| % > 125 pg/mL | 77 | - |
| % > 450 pg/mL | - | 91 |
| N | 47 | 22 |
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CHF Population - All
| NYHA Functional Class | | | | | |
| --- | --- | --- | --- | --- | --- |
| | All CHF | NYHA I | NYHA II | NYHA III | NYHA IV |
| Median | 1422.0 | 659.2 | 1087.3 | 2546.0 | 2717.1 |
| Mean | 3693.0 | 2762.0 | 2361.1 | 4500.3 | 6725.8 |
| SD | 7911.8 | 9591.0 | 3556.1 | 7391.8 | 11880.1 |
| 5th Percentile | 59.3 | 47.9 | 29.4 | 117.4 | 76.4 |
| 95th Percentile | 11398.6 | 9864.6 | 9561.9 | 12127.1 | 20855.8 |
| % > Cutoff | 85 | 76 | 84 | 90 | 90 |
| Minimum | 17.6 | 21.7 | 17.6 | 60.3 | 50.6 |
| Maximum | 70025.3 | 70025.3 | 19397.4 | 57436.0 | 63515.3 |
| N | 227 | 54 | 73 | 70 | 30 |
CHF Population - Males
| NYHA Functional Class | | | | | |
| --- | --- | --- | --- | --- | --- |
| | All CHF | NYHA I | NYHA II | NYHA III | NYHA IV |
| Median | 1710.7 | 938.6 | 1543.8 | 3229.0 | 2717.1 |
| Mean | 4273.6 | 3333.53 | 2925.5 | 5047.3 | 8627.2 |
| SD | 9109.3 | 10814.4 | 4004.6 | 8249.2 | 15926.0 |
| 5th Percentile | 60.3 | 57.8 | 33.1 | 122.1 | 76.4 |
| 95th Percentile | 13600.1 | 9864.6 | 9561.9 | 12127.1 | 63515.3 |
| % > Cutoff | 86 | 81 | 84 | 92 | 87 |
| Minimum | 21.7 | 21.7 | 27.3 | 60.3 | 76.4 |
| Maximum | 70025.3 | 70025.3 | 19397.4 | 57436.0 | 63515.3 |
| N | 158 | 42 | 49 | 52 | 15 |
CHF Population - Females
| NYHA Functional Class | | | | | |
| --- | --- | --- | --- | --- | --- |
| | All CHF | NYHA I | NYHA II | NYHA III | NYHA IV |
| Median | 933.5 | 232.6 | 550.2 | 1933.5 | 2754.5 |
| Mean | 2363.5 | 761.6 | 1208.8 | 2920.1 | 4824.3 |
| SD | 3725.4 | 1301.7 | 2013.8 | 3749.6 | 5565.2 |
| 5th Percentile | 50.6 | 47.9 | 24.4 | 103.2 | 50.6 |
| 95th Percentile | 10375.0 | 4723.5 | 2524.6 | 13287.1 | 20855.8 |
| % > Cutoff | 81 | 58 | 83 | 83 | 93 |
| Minimum | 17.6 | 47.9 | 17.6 | 103.2 | 50.6 |
| Maximum | 20855.8 | 4723.5 | 10029.4 | 13287.1 | 20855.8 |
| N | 69 | 12 | 24 | 18 | 15 |
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N. Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
