SYNCHRON SYSTEMS HIGH SENSITIVITY CARDIAC C-REACTIVE PROTEIN (CRPH) REAGENT

K070626 · Beckman Coulter, Inc. · NQD · May 4, 2007 · Immunology

Device Facts

• Record ID: K070626
• Device Name: SYNCHRON SYSTEMS HIGH SENSITIVITY CARDIAC C-REACTIVE PROTEIN (CRPH) REAGENT
• Applicant: Beckman Coulter, Inc.
• Product Code: NQD · Immunology
• Decision Date: May 4, 2007
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.5270
• Device Class: Class 2

Indications for Use

High Sensitivity Cardiac C-Reactive Protein (CRPH) reagent, when used in conjunction with SYNCHRON LX 20 PRO System. UniCel® DxC 600/800 System(s) and SYNCHRON® Systems CAL 5 Plus, is intended for the quantitative determination of C-Reactive Protein in human serum or plasma by rate turbidimetry.

Device Story

In vitro diagnostic reagent for quantitative determination of C-Reactive Protein (CRP) in human serum or plasma. Uses near-infrared particle immunoassay rate turbidimetry; anti-CRP antibody-coated particles bind to CRP in patient samples to form insoluble aggregates, increasing turbidity. Operated on SYNCHRON LX 20 PRO or UniCel DxC 600/800 systems by laboratory personnel. Output is a quantitative CRP concentration value. Healthcare providers use results to assess inflammation, stratify cardiovascular disease risk, and determine prognosis for recurrent events in coronary syndrome patients. Benefits include objective clinical data for patient management and risk stratification.

Clinical Evidence

Bench testing only. Precision evaluated per CLSI EP5-A2 (N=80, total CV 2.8-5.3%). Linearity verified per CLSI EP6-A (0.2-80.0 mg/L, r²=0.9977). Analytical sensitivity 0.11 mg/L; functional sensitivity 0.18 mg/L. Method comparison with predicate (N=269) showed Deming regression Y=1.048X+0.024 (r=0.9899). Matrix comparison (serum vs plasma) showed high correlation (r>0.999). No clinical prospective/retrospective studies performed; clinical utility supported by AHA/CDC guidelines.

Technological Characteristics

Particle-enhanced immunonephelometry assay. Reagents: particle-bound goat/mouse anti-CRP antibodies, buffer, sodium azide, bovine serum albumin. Measuring range: 0.2-80.0 mg/L; extended range: 60.0-380.0 mg/dL. Traceable to CRM 470. Instruments: Synchron LX PRO and UniCel DxC 600/800. Connectivity: system-integrated. Sterilization: N/A (reagent kit).

Indications for Use

Indicated for quantitative determination of C-Reactive Protein (CRP) in human serum or plasma. Used as an aid in evaluation of stress, trauma, infection, inflammation, surgery, and associated diseases. Indicated for identification and stratification of individuals at risk for future cardiovascular disease and as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndrome.

Regulatory Classification

Identification

A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.

Predicate Devices

• Dade Behring CardioPhase hsCRP (K033908)
• Synchron Systems High Sensitivity CRPH Reagent (K010597)

Submission Summary (Full Text)

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

A. 510(k) Number:
k070626

B. Purpose for Submission:
Add indication for use for evaluation of cardiac disease on already cleared product- k010597

C. Measurand:
C-Reactive Protein

D. Type of Test:
Quantitative rate turbidimetry assay

E. Applicant:
Beckman Coulter Inc.

F. Proprietary and Established Names:
Synchron Systems High Sensitivity Cardiac C-Reactive Protein (CRPH) Reagent

G. Regulatory Information:
1. Regulation section:
21CFR 866.5270
2. Classification:
Class II
3. Product code:
NQD (Cardiac C-Reactive Protein, Antigen, Antiserum, and Control)
4. Panel:
Immunology (82)

H. Intended Use:
1. Intended use(s):
See Indications for Use below.

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2. Indication(s) for use:

High Sensitivity Cardiac C-Reactive Protein (CRPH) Reagent, when used in conjunction with Synchron LX PRO System, UniCel DxC 600/800 System(s) and Synchron Systems CAL 5 Plus, is intended for the quantitative determination of C-Reactive protein (CRP) in human serum or plasma by rate turbidimetry.

Measurement of C-Reactive protein (CRP) aids in evaluation of stress, trauma, infection, inflammation, surgery and associated diseases. Cardiac CRP assays are indicated for use as an aid in the identification and stratification of individuals at risk for future cardiovascular disease. When used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, CRP may be useful as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndrome.

3. Special conditions for use statement(s):

For prescription use

4. Special instrument requirements:

Synchron LX PRO System and UniCel DxC 600/800 System(s).

I. Device Description:

Each kit contains the following items: Two CRPH reagent cartridges (2x200 tests) and one lot-specific parameter card.

Reagent constituents:

- CRP Antibody (particle bound goat and mouse anti-CRP antibody) – 17.3 mL in compartment B
- Reagent buffer – 47.8 mL in compartment A
- Sodium Azide (used as a preservative) – < 0.1% (w/w)
- Bovine Serum Albumin – 0.125% (w/v)
- Other non-reactive chemicals necessary for optimal system performance

J. Substantial Equivalence Information:

1. Predicate device name(s):

Dade Behring CardioPhase High Sensitivity CRP and Synchron Systems High Sensitivity CRPH Reagent

2. Predicate 510(k) number(s):

k033908, k010597

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3. Comparison with predicate:

| Similarities and Differences between candidate device and Dade Behring CardioPhase High Sensitivity CRP (Predicate device)-k033908 | | |
| --- | --- | --- |
| Item | Synchron Systems High Sensitivity Cardiac CRPH (Candidate device) | Dade Behring CardioPhase High Sensitivity CRP (Predicate device) |
| Indications for Use | Measurement of C-Reactive protein (CRP) aids in evaluation of stress, trauma, infection, surgery and associated diseases. Cardiac CRP assays are indicated for use as an aid in the identification and stratification of individuals at risk for future cardiovascular disease. When used in conjunction with traditional clinical laboratory evaluation of acute coronary syndrome, CRP may be useful as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndrome. | Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. Measurements may also be used as an aid in the identification of individuals at risk for future cardiovascular disease. High sensitivity CRP (hsCRP) measurements when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes may be useful as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndromes. |
| Instruments | Synchron LX PRO System and UniCel DxC 600/800 System(s). | Dade Behring BN Systems |
| Assay Type | Particle enhanced immunonephelometry | Particle enhanced immunonephelometry |
| Antibodies | Particle bound Anti-CRP antibody; goat and mouse antibodies | Particle bound Anti-CRP antibody; mouse |
| Expected Values | < 7.48 mg/L in 95% of the population tested. The expected value is based on a population of 551 apparently healthy adults in Southern California. | Expected values for healthy individuals as noted in the literature is <3 mg/L. The normal range of CRP in the serum of 2147 apparently healthy individuals using the CardioPhase hsCRP Assay was found to be 90% 1.69 mg/L 95% 2.87 mg/L As CRP is a nonspecific indicator for a wide range of disease processes, and as the reference individuals are affected by many factors that may differ for each population studied, each laboratory should determine its own reference interval. |
| Reference standards | CRM 470 | CRM 470 |

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| Similarities and Differences between candidate device and Synchron Systems High Sensitivity CRPH (predicate device)- k010597 | | |
| --- | --- | --- |
| Item | Synchron Systems High Sensitivity Cardiac CRPH (Candidate device) | Synchron Systems High Sensitivity CRPH (Predicate device) |
| Indications for Use | Cardiac risk assessment and injury/inflammation | Injury/inflammation |
| Assay Type | Particle enhanced immunonephelometry | same |
| Antibodies | Particle bound Anti-CRP antibody; goat and mouse antibodies | same |
| Expected Values | < 7.48 mg/L | same |
| Reference standards | CRM 470 | same |
| Measuring Range | 0.2 to 80.0 mg/L | same |
| Extended Range | 60.0 to 380.0 mg/dL | same |
| Analytic Sensitivity | 0.11 mg/L | same |
| Functional Sensitivity | 0.18 mg/L | same |
| Sample Type | Serum, heparinized and EDTA plasma | same |
| Sample size | 10 μL | 20 μL |

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K. Standard/Guidance Document Referenced (if applicable):

1. CLSI Guideline, EP5-A2 Evaluation of Precision Performance of Clinical Chemistry Devices; Approved Guideline Second edition
2. CLSI Guideline, EP6-A Evaluation of the Linearity of Quantitative Analytical Methods; Approved Guideline
3. CLSI Guideline, EP9-A2 Method Comparison and Bias Estimation Using Patient Samples; Approved Guideline Second edition

L. Test Principle:

Synchron Systems High Sensitivity Cardiac CRP is based on the highly sensitive near infrared particle immunoassay rate methodology. An anti-CRP antibody-coated particle binds to CRP in the patient sample resulting in the formation of insoluble aggregates causing turbidity.

The chemical reaction scheme is as follows:

C-reactive protein (sample) + Particle bound anti-CRP (antibody) ⇒ [C-reactive protein (sample)-antibody complex]

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

Within-run and total imprecision studies were designed using CLSI EP5-A2 guideline. Three levels of serum based controls were run twice a day, in duplicate, for 20 days on the UniCel DxC system. Mean, SD, and % CV are calculated and shown in the tables below:

Within-run imprecision

| Sample | N | Mean (mg/L) | SD (mg/L) | % CV |
| --- | --- | --- | --- | --- |
| Level 1 | 80 | 0.630 | 0.019 | 3.1 |
| Level 2 | 80 | 13.68 | 0.222 | 1.6 |
| Level 3 | 80 | 56.39 | 0.907 | 1.6 |

Total imprecision

| Sample | N | Mean (mg/L) | SD (mg/L) | % CV |
| --- | --- | --- | --- | --- |
| Level 1 | 80 | 0.630 | 0.033 | 5.3 |
| Level 2 | 80 | 13.68 | 0.381 | 2.8 |
| Level 3 | 80 | 56.39 | 1.823 | 3.2 |

b. Linearity/assay reportable range:

i.) The linearity study was designed using the CLSI EP6-A guideline. Serial dilutions of high serum samples were used on the Synchron LX20 PRO system for this study.

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The linear regression of the correlation was as follows:

$$
Y = 1.0051 X + 0.1415, r^2 = 0.9977
$$

A low sample with concentration of 13.6 mg/L with serial dilutions was also tested to show the low end linearity and the linear regression was as follows:

$$
Y = 0.9861 X + 0.0941, r^2 = 0.9993
$$

The sponsor claimed a linear range of 0.2 to 80.0 mg/L.

ii.) A dilution study was done to verify the extended range on the candidate device. Seventeen (17) serum samples with different CRP concentrations were tested on the Synchron LX20 PRO system using the Synchron Systems Cardiac High Sensitivity CRPH Reagent (candidate) and the Synchron Systems High Sensitivity CRPH Reagent (predicate). The results demonstrated that the two assays agreed within ± 15%. The sponsor claimed that the extended (ORDAC) range is 60.0 to 380.0 mg/L.

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Synchron Systems Cardiac High Sensitivity CRPH Reagent is traceable to CRM 470 reference materials.

d. Detection limit:

i.) An analytical sensitivity (limit of blank) study was performed using several low standards and the Synchron LX 20 PRO System. Analytical sensitivity was defined as the lowest measurable concentration which can be distinguished from zero with 95% confidence. The standards were run in 20 replicates and the mean and SD was calculated based on the observed results. The sponsor claimed that the analytical sensitivity of the candidate device is 0.11 mg/L.

ii.) A functional sensitivity (limit of quantitation) study was performed using serum samples and the UniCel DxC System. The functional sensitivity was defined as the lowest concentration that can be measured with an inter-assay CV of 20%. Six serum samples with different CRP concentrations were run in duplicates of 10 and the mean and SD were calculated based on the observed results. The sponsor claimed that the functional sensitivity of the candidate device is 0.18 mg/L.

e. Analytical specificity:

Interference testing was not repeated and remained unchanged as the previously cleared predicate device, Synchron Systems High Sensitivity CRP (k010597)

f. Assay cut-off:

Not Applicable

2. Comparison studies:

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a. Method comparison with predicate device:

Method comparison studies were designed using CLSI EP9-A as a guideline and employed Deming regression analysis to analyze the data. The correlation test results were obtained using the Dade Behring CardioPhase High Sensitivity CRP (predicate) on the BN System and the Synchron System High Sensitivity Cardiac CRPH reagent (candidate) on the UniCel DxC System. 269 serum patient samples ranging from 0.2 to 80.0 mg/L were utilized for this study and no samples were diluted or fortified. The Deming regression correlation is as follows:

$$
Y = 1.048 X + 0.024, r = 0.9899
$$

A separate regression was calculated for samples ranging from 0.2 to 10 mg/L (cardiac range) and Deming regression correlation is as follows:

$$
Y = 1.030 - 0.008, r = 0.9910, N = 149.
$$

(Y = candidate device, X = predicate device)

b. Matrix comparison:

Matrix comparison studies using 47 healthy individuals with paired serum, EDTA, Lithium Heparin and Sodium Heparin were analyzed using the Synchron System High Sensitivity Cardiac CRPH reagent (candidate) on the Synchron LX 20 PRO System. Samples ranged from 0.221 to 23.9 mg/L. Deming regression analysis was used to evaluate the results.

For serum vs Sodium heparin plasma: Y = 0.984 X + 0.049, r = 0.9997

For serum vs Lithium heparin plasma: Y = 1.017 X - 0.012, r = 0.9998

For serum vs EDTA plasma: Y = 0.982 X + 0.021, r = 0.9999

(X = serum results)

3. Clinical studies:

a. Clinical Sensitivity:

Not Applicable

b. Clinical specificity:

Not Applicable

c. Other clinical supportive data (when a. and b. are not applicable):

4. Clinical cut-off:

Not Applicable

5. Expected values/Reference range:

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i.) AHA/CDC* recommends the following cardiovascular disease risk assessment guidelines for CRP.

| Risk Level | CRP (mg/L) |
| --- | --- |
| Low | < 1.0 |
| Average | 1.0 – 3.0 |
| High | > 3.0 |

* Pearson, T.A, Mensag, G.A., Alexander RW, Anderson JL, Canon RO 3rd, Criqui M, Fadl YY., Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F, Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A statement for Healthcare Professional From the Centers for Disease Control and Prevention and the American Heart Association Circulation. 107:499-511 (2003)

ii.) The reference range interval values for CRP were based on a population of 551 apparently healthy, non-smoking, ≥ 18 years of age, male and female adults from a Southern California blood bank. The expected normal range is &lt; 7.48 mg/L in 95% of the population tested. (See k010597).

## N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

## O. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.