(112 days)
The Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma (lithium heparin, sodium heparin or K2 EDTA) on the Atellica® CH Analyzer.
Measurements from Atellica® CH High Sensitivity C -Reactive Protein 2 (hCRP2) may be used as an aid in identification of individuals at risk for future cardiovascular disease. Measurement of hCRP2, when used in coniunction 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.
The Atellica CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay is used for the quantitative determination of C-Reactive protein in human serum and plasma using the Atellica CH analyzer. This device is two ready-to-use reagent packs consisting of 23.1mL Phosphate buffer, polidocanol (1.9g/L), and sodium azide (0.1%) in Pack 1 and 12.3mL Mouse anti-CRP monoclonal antibodies (13mg/L), polystyrene particles (1g/L), human albumin (0.05%) and sodium azide (<0.1%) in Pack 2. This product consists of two (2) kits consisting of 360 tests each for a total of 720 tests.
Polystyrene particles coated with monoclonal antibodies specific to human CRP are aggregated when mixed with samples containing CRP. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.
The system automatically performs the following steps:
-
- For serum/plasma, dispenses 30 µL of primary sample and 90 µL of Atellica CH Diluent into a dilution cuvette.
-
- Dispenses 100 µL of Reagent 1 into a reaction cuvette.
-
- Dispenses 3 µL of pre-diluted sample into a reaction cuvette.
-
- Dispenses 45 µL of Reagent 2 into a reaction cuvette.
-
- Mixes and incubates the mixture at 37°C.
-
- Measures the absorbance after Reagent 2 addition.
-
- Reports results.
Atellica CH High-Sensitivity C-Reactive Protein 2 (hCRP2) assay is used in conjunction with the Atellica CH Analyzer and Atellica CH Protein 2 Calibrator (PROT2 CAL)
Here's a summary of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) summary:
Device: Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay
1. Table of Acceptance Criteria and Reported Device Performance:
| Performance Characteristic | Acceptance Criteria (Design Goal) | Reported Device Performance |
|---|---|---|
| Detection Capability | ||
| Limit of Blank (LoB) | LoB ≤ Limit of Detection (LoD) | 0.06 mg/L |
| Limit of Detection (LoD) | LoD ≤ Limit of Quantitation (LoQ) | 0.11 mg/L |
| Limit of Quantitation (LoQ) | ≤ 0.16 mg/L (with < 20% deviation) | 0.16 mg/L |
| Precision | Undefined numerical criteria provided, but demonstrated across various concentration levels. | Repeatability (CV%) range: 0.5% - 2.1%. Within-Lab (CV%) range: 0.8% - 2.5%. (Based on 80 replicates per specimen) |
| Reproducibility | Undefined numerical criteria provided, but demonstrated across multiple sites/instruments/lots. | Total Reproducibility (CV%) range: 0.9% - 2.5%. (Based on 225 replicates per specimen) |
| Assay Comparison | Correlation coefficient (r) ≥ 0.950, Slope of 1.00 ± 0.05 (compared to BN ProSpec CardioPhase hsCRP) | r = 0.999, Slope = 0.96 (from y = 0.96x + 0.03 mg/L). Meets criteria for correlation and slope (0.96 is within 1.00 ± 0.05). |
| Specimen Equivalency | Undefined numerical criteria for regression, but strong correlation visually implied acceptable. | Sodium Heparin vs. Serum: y = 1.07x - 0.02 mg/L (r = 0.998) Potassium EDTA vs. Serum: y = 0.97x - 0.03 mg/L (r = 0.997) Lithium Heparin vs. Serum: y = 1.07x - 0.03 mg/L (r = 0.998). Strong correlations (r values near 1) indicate good equivalency. |
| Interferences (HIL) | ≤ 10% interference from hemoglobin, bilirubin, and lipemia. | Hemoglobin: 0% to 4% bias at 10 g/L Bilirubin, conjugated: -1% bias at 684 µmol/L Bilirubin, unconjugated: -1% to 0% bias at 684 µmol/L Lipemia (Intralipid®): -7% to -4% bias at 30 g/L. All biases are ≤ 10%. |
| Non-interfering Substances | ≤ 10% bias for Rheumatoid factors. | Rheumatoid factors: -1% to 0% bias at 500 IU/mL. All biases are ≤ 10%. |
| High-Dose Hook Effect | Not explicitly stated as a numerical criterion, but designed to avoid hook effect within reportable range. | High C-reactive protein levels as high as 1300.00 mg/L will read > 9.50 mg/L (which is the upper limit of the measuring interval). This indicates the assay correctly identifies concentrations above the measuring interval and avoids a hook effect within the intended range. |
2. Sample Size Used for the Test Set and Data Provenance:
- Detection Capability:
- LoB: 3 reagent lots, 6 blank samples, 5 replicates per sample = 90 determinations.
- LoD: 495 determinations (270 blank, 225 low-level replicates) using 3 reagent lots.
- LoQ: 5 native low analyte serum samples, 5 replicates each = 25 determinations.
- Precision (Repeatability/Within-Lab): 80 replicates per specimen (5 serum samples + 1 QC, total 6 specimens).
- Reproducibility (Multi-site/Multi-lot): 225 replicates per specimen (5 serum samples + 3 QCs, total 8 specimens).
- Assay Comparison (Method Comparison): 100 patient samples.
- Specimen Equivalency: 55 patient samples for each specimen type (Sodium Heparin, Potassium EDTA, Lithium Heparin).
- Interferences (HIL & Non-interfering Substances): Not explicitly stated, but typically involves a smaller number of samples spiked with interferents at multiple analyte concentrations.
Data Provenance: Not explicitly stated, but the sample types are human serum and plasma, diluted with Atellica CH diluent (saline) or enriched as needed. This usually implies a mix of commercially sourced and/or in-house collected human samples. There is no information regarding the country of origin or whether the studies were retrospective or prospective.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
This device is an in vitro diagnostic test for C-Reactive Protein (CRP) concentration. The "ground truth" for a quantitative assay like this is typically established by:
- Reference methods/standards (e.g., ERM-DA474/IFCC for CRP, as mentioned).
- Comparative analysis against a legally marketed predicate device (BN ProSpec CardioPhase hsCRP).
- Standard preparation and gravimetric/volumetric assurance for spiked samples or known concentrations.
Therefore, "experts" in the sense of clinical reviewers or pathologists establishing a diagnostic ground truth is not applicable here. The accuracy of the measurements is compared against established analytical criteria and methodologies.
4. Adjudication Method for the Test Set:
Not applicable in the context of this type of IVD performance study, as there is no subjective interpretation requiring adjudication of results from different observers. The output is a quantitative value (mg/L).
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done:
No, an MRMC comparative effectiveness study was not done. This type of study is relevant for imaging or diagnostic tests where human interpretation plays a significant role and AI assistance might influence reader performance. For a quantitative in vitro diagnostic assay like high-sensitivity CRP, the measurement is automated and objective.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:
Yes, the studies described (Detection Capability, Precision, Reproducibility, Assay Comparison, Specimen Equivalency, Interferences, High-Dose Hook Effect) are all standalone performance evaluations of the Atellica CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay as an automated laboratory test on the Atellica CH Analyzer. The device is intended for in vitro diagnostic use, meaning it operates without direct human interpretive input beyond running the test and reading the numerical result.
7. The Type of Ground Truth Used:
The ground truth for this device is established through:
- Analytical Standards: The assay is traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference material ERM-DA474/IFCC, which serves as a primary ground truth for CRP concentration.
- Predicate Device Comparison: The performance is compared against a legally marketed predicate device (BN ProSpec CardioPhase hsCRP assay), where the predicate's measurements serve as a comparative standard.
- Reference Intervals: Expected values for cardiovascular risk prediction are based on established clinical guidelines (Pearson TA et al., 2003).
- Spiked Samples: For interference studies, known concentrations of interfering substances are added to samples, and the known concentration of the analyte is the ground truth.
8. The Sample Size for the Training Set:
Not explicitly stated in the 510(k) summary. For a device like this, the "training set" would refer to the samples used during the development and optimization phase of the assay (e.g., reagent formulation, calibration curve development), rather than a machine learning training set. The approval document focuses on the validation or test sets.
9. How the Ground Truth for the Training Set Was Established:
Similar to point 7, the ground truth for potential "training" (development/optimization) would involve analytical standards (like ERM-DA474/IFCC), purified CRP, and well-characterized human serum/plasma samples, often with known CRP concentrations determined by reference methods or gravimetric/volumetric preparation. The goal would be to develop a robust assay that accurately measures CRP across its analytical range.
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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services logo on the left and the FDA logo on the right. The FDA logo is in blue and includes the letters "FDA" followed by the words "U.S. Food & Drug Administration".
January 18, 2024
Siemens HealthCare Diagnostics Inc. Anthony Calabro Regulatory Affairs Specialist 500 GBC Drive Newark, Delaware 19714
Re: K233242
Trade/Device Name: Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) Regulation Number: 21 CFR 866.5270 Regulation Name: C-Reactive Protein Immunological Test System Regulatory Class: Class II Product Code: NQD Dated: October 20, 2023 Received: October 20, 2023
Dear Anthony Calabro:
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 (the 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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
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Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
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 Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Paula V. Caposino -S
Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
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Indications for Use
Submission Number (if known)
K233242 Device Name
Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2)
Indications for Use (Describe)
The Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma (lithium heparin, sodium heparin or K2 EDTA) on the Atellica® CH Analyzer.
Measurements from Atellica® CH High Sensitivity C -Reactive Protein 2 (hCRP2) may be used as an aid in identification of individuals at risk for future cardiovascular disease. Measurement of hCRP2, when used in coniunction 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.
Type of Use (Select one or both. as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
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This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.
The assigned 510(k) Number is: K233242
1. Date Prepared
January 18, 2024
2. Applicant Information
| Contact: | Anthony CalabroRegulatory Affairs Specialist |
|---|---|
| Address: | Siemens Healthcare Diagnostics Inc500 GBC DriveNewark, DE 19714 |
| Email: | anthony_calabro@siemens-healthineers.com |
3. Regulatory Information
Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay
Trade Name: Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) Common Name: Cardiac C-Reactive Protein, Antiserum, and Control Classification Name: C-reactive protein immunological test system FDA Classification: Class II Review Panel: Immunology Product Code: NQD Regulation Number: 21 CFR 866.5270
4. Predicate Device Information
Predicate Device Name: BN ProSpec System CardioPhase hsCRP 510(k) Number: K212559
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5. Intended Use / Indications For Use
The Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma (lithium heparin, sodium heparin or K2 EDTA) on the Atellica® CH Analyzer.
Measurements from Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) may be used as an aid in identification of individuals at risk for future cardiovascular disease. Measurement of hCRP2, 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.
Special Conditions for Use Statement: For Prescription Use Only
6. Device Description
The Atellica CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay is used for the quantitative determination of C-Reactive protein in human serum and plasma using the Atellica CH analyzer. This device is two ready-to-use reagent packs consisting of 23.1mL Phosphate buffer, polidocanol (1.9g/L), and sodium azide (0.1%) in Pack 1 and 12.3mL Mouse anti-CRP monoclonal antibodies (13mg/L), polystyrene particles (1g/L), human albumin (0.05%) and sodium azide (<0.1%) in Pack 2. This product consists of two (2) kits consisting of 360 tests each for a total of 720 tests.
Polystyrene particles coated with monoclonal antibodies specific to human CRP are aggregated when mixed with samples containing CRP. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.
The system automatically performs the following steps:
-
- For serum/plasma, dispenses 30 µL of primary sample and 90 µL of Atellica CH Diluent into a dilution cuvette.
-
- Dispenses 100 µL of Reagent 1 into a reaction cuvette.
-
- Dispenses 3 µL of pre-diluted sample into a reaction cuvette.
-
- Dispenses 45 µL of Reagent 2 into a reaction cuvette.
-
- Mixes and incubates the mixture at 37°C.
-
- Measures the absorbance after Reagent 2 addition.
-
- Reports results.
Atellica CH High-Sensitivity C-Reactive Protein 2 (hCRP2) assay is used in conjunction with the Atellica CH Analyzer and Atellica CH Protein 2 Calibrator (PROT2 CAL)
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7. Purpose of Submission
The purpose of this submission is a premarket notification for a new device: Atellica CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay.
8. Comparison of Candidate Device and Predicate Device
The table below describes the similarities and differences between the Atellica CH High Sensitivity C-Reactive Protein 2 assay (Candidate Device) and the BN ProSpec CardioPhase hsCRP (Predicate Device).
Substantial equivalence was demonstrated by testing several performance characteristics including measuring interval, expected values, reference interval, precision, method comparison, interference, and specimen equivalence by method comparison.
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| Feature | Candidate Device | Predicate Device |
|---|---|---|
| Atellica® CH High Sensitivity C-ReactiveProtein 2 (hCRP2) | BN ProSpec CardioPhase hsCRP | |
| Intended Use | The Atellica® CH High SensitivityC-Reactive Protein 2 (hCRP2) assay isfor in vitro diagnostic use in thequantitative determination of theconcentration of C-Reactive Protein(CRP) in human serum and plasma(lithium heparin, sodium heparin orK2 EDTA) on the Atellica® CHAnalyzer.Measurements from Atellica® CHHigh Sensitivity C-Reactive Protein 2(hCRP2) may be used as an aid inidentification of individuals at risk forfuture cardiovascular disease.Measurement of hCRP2, when usedin conjunction with traditional clinicallaboratory evaluation of acutecoronary syndromes, may be usefulas an independent marker ofprognosis for recurrent events inpatients with stable coronary diseaseor acute coronary syndromes. | CardioPhase® hsCRP is an in-vitrodiagnostic reagent for the quantitativedetermination of C-reactive protein (CRP)in human serum, and heparin and EDTAplasma by means of particle enhancedimmunonephelometry using the BN II andBN ProSpec® System. In acute phaseresponse, increased levels of a number ofplasma proteins, including C-reactiveprotein, is observed. Measurement of CRPis useful for the detection and evaluationof infection, tissue injury, inflammatorydisorders and associated diseases*. Highsensitivity CRP (hsCRP) measurementsmay be used as an independent riskmarker for the identification of individualsat risk for future cardiovascular disease.Measurements of hsCRP, when used inconjunction with traditional clinicallaboratory evaluation of acute coronarysyndromes, may be useful asan independent marker of prognosis forrecurrent events, in patients with stablecoronary disease or acute coronarysyndromes. |
| Sample Type | Human serum and plasma (lithium heparin,sodium heparin, K2 EDTA) | Human Serum, and heparin and K2 EDTAplasma |
| Units of Measure | mg/L | Same |
| Assay Range / MeasuringInterval | 0.16-9.50 mg/L | 0.155 – 9.95 mg/L(calibrator lot dependent) |
| Expected Values | Risk for cardiovascular diseaseprediction:< 1.00 mg/L are low risk1.00 mg/L and 3.00 mg/L areaverage risk> 3.00 mg/L are high risk | Same |
| Feature | Candidate Device | Predicate Device |
| Atellica® CH High Sensitivity C-ReactiveProtein 2 (hCRP2) | BN ProSpec CardioPhase hsCRP | |
| Assay Principle | Particle enhanced immunonephelometry | Same |
| Standardization | ERM-DA474/IFCC | Same |
| Calibration | Multi-Level calibration | Same |
| Calibrators | Atellica CH Protein 2 Calibrator(PROT2 CAL) | N Rheumatology Standard SL |
| Reagents | Two liquid reagents, ready to use | Same |
| Composition | Pack 1: 23.1 mLPhosphate buffer; polidocanol (1.9g/L); sodium azide (0.1%)Pack 2: 12.3 mLMouse anti-CRP monoclonal antibodies (13mg/L); polystyreneparticles (1 g/L); human albumin(0.05%); sodium azide (<0.1%) | Same |
| Interferences | Bilirubin, Conjugated:No Interference ≤ 0.4g/LBilirubin, Unconjugated:No Interference ≤ 0.4g/LLipemia:No Interference ≤ 30g/LHemoglobin:No Interference ≤ 10g/L | Bilirubin:No Interference ≤ 0.6g/LTriglycerides:No Interference ≤ 16g/LHemoglobin:No Interference ≤ 10g/L |
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9. Standard/Guidance Document References
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The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:
• Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition. (CLSI EP05-A3).
· Interference Testing in Clinical Chemistry (CLSI EP07-ED3).
· Measurement Procedure Comparison and Bias Estimation Using Patient Samples (CLSIEP09c-ED3).
• Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline-Second Edition (EP17-A2).
- · Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline (CLSI EP25-A).
• Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition (CLSI EP28-A3c).
The following FDA guidance was followed:
Guidance for Industry and FDA Staff: Review Criteria for Assessment of C-Reactive Protein (CRP), High Sensitivity C-Reactive Protein (hsCRP) and Cardiac C-Reactive Protein (cCRP) Assays. Issued on September 22, 2005.
Performance Characteristics for Atellica ® CH High Sensitivity C-Reactive 10. Protein 2 (hCRP2)
10.1 Detection Capability
The Limit of Blank (LoB) corresponds to the highest measurement result that is likely to be observed for a blank sample. The assay is designed to have an LoB ≤ Limit of Detection (LoD). LoB was conducted with three (3) reagent lots, six (6) blank samples, and five (5) replicates per sample.
The Limit of Detection (LoD) corresponds to the lowest concentration of c-reactive protein that can be detected with a probability of 95%. The assay is designed to have an LoD ≤ Limit of Quantitation(LoQ). LoD was determined using 495 determinations with 270 blank and 225 low level replicates. Blank samples were 5 lots of Atellica CH diluent and 1 lot of 6% BSA. The 5 low level serum samples were 5 separate human serum samples diluted with Atellica CH diluent targeted to approximately 0.05 mg/L. Three reagent lots were used.
The Limit of Quantitation (LoQ) corresponds to the lowest concentration of c-reactive protein that met the required analyte level but did not reach 20% deviation The assay is designed to have an LoQ of ≤ 0.16mg/L. LoQ samples were prepared by diluting 5 native low analyte serum samples with Atellica CH diluent (saline) to obtain approximately 0.16mg/L. Five replicates of each sample were measured.
Detection capability was determined in accordance with CLSI Documents EP17-A2.
The following results were obtained:
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| Specimen Type | Detection Capability | Result mg/L |
|---|---|---|
| Serum/Plasma | LoB | 0.06 |
| Serum/Plasma | LoD | 0.11 |
| Serum/Plasma | LoQ | 0.16 |
10.2 Precision
Precision was determined in accordance with CLSI Document EP05-A3. Samples were assayed on the Atellica CH Analyzer in duplicate in 2 runs per day for 20 days. The following results were obtained.
| Specimen Type | N | Repeatability | Within-Lab | |||
|---|---|---|---|---|---|---|
| Meanmg/L | SDmg/L | CV(%) | SDmg/L | CV(%) | ||
| QC1 | 80 | 0.81 | 0.017 | 2.1 | 0.020 | 2.5 |
| Serum 1 | 80 | 1.06 | 0.015 | 1.4 | 0.017 | 1.6 |
| Serum 2 | 80 | 2.55 | 0.021 | 0.8 | 0.048 | 1.9 |
| Serum 3 | 80 | 2.90 | 0.015 | 0.5 | 0.023 | 0.8 |
| Serum 4 | 80 | 4.12 | 0.030 | 0.7 | 0.084 | 2.0 |
| Serum 5 | 80 | 8.74 | 0.065 | 0.7 | 0.110 | 1.3 |
10.3 Reproducibility
Reproducibility was determined in accordance with CLSI Document EP05-A3. Samples were assayed with 5 replicates per run for 5 days using 3 instruments/sites and 3 reagent lots. The data was analyzed to calculate the following components of precision: repeatability, between-day, between-lot, between-instrument, and reproducibility (total). The following results were obtained.
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| Reproducibility | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Repeatability | Between Day | Between Lot | Between Instrument | Total Reproducibility | ||||||||
| ASSAY | SAMPLE | N | mg/L | SD | CV | SD | CV | SD | CV | SD | CV | SD | CV |
| mg/L | % | mg/L | % | mg/L | % | mg/L | % | mg/L | % | ||||
| hCRP2 | QC1 | 225 | 0.72 | 0.012 | 1.6 | 0.001 | 0.2 | 0.005 | 0.6 | 0.013 | 1.8 | 0.018 | 2.5 |
| hCRP2 | Serum 1 | 225 | 1.06 | 0.017 | 1.6 | 0.008 | 0.8 | 0.000 | 0.0 | 0.014 | 1.3 | 0.023 | 2.2 |
| hCRP2 | QC2 | 225 | 1.86 | 0.012 | 0.6 | 0.008 | 0.4 | 0.007 | 0.4 | 0.017 | 0.9 | 0.023 | 1.2 |
| hCRP2 | Serum 2 | 225 | 2.91 | 0.023 | 0.8 | 0.014 | 0.5 | 0.000 | 0.0 | 0.016 | 0.5 | 0.032 | 1.1 |
| hCRP2 | QC3 | 225 | 5.63 | 0.030 | 0.5 | 0.018 | 0.3 | 0.026 | 0.5 | 0.029 | 0.5 | 0.052 | 0.9 |
| hCRP2 | Serum 3 | 225 | 3.98 | 0.021 | 0.5 | 0.018 | 0.4 | 0.023 | 0.6 | 0.030 | 0.7 | 0.047 | 1.2 |
| hCRP2 | Serum 4 | 225 | 7.12 | 0.045 | 0.6 | 0.031 | 0.4 | 0.017 | 0.2 | 0.064 | 0.9 | 0.086 | 1.2 |
| hCRP2 | Serum 5 | 225 | 8.56 | 0.059 | 0.7 | 0.062 | 0.7 | 0.002 | 0.0 | 0.047 | 0.5 | 0.098 | 1.1 |
Assay Comparison 10.4
The Atellica CH High Sensitivity C-Reactive Protein 2 assay was designed to have correlation coefficient of ≥ 0.950 and a slope of 1.00 ± 0.05 compared to the BN ProSpec CardioPhase hsCRP assay. The following results were obtained using the weighted Deming regression model in accordance with CLSI EP09c.
| SpecimenType | Comparison Assay (x) | Regression Equation | Sample Range(mg/L) | N | r |
|---|---|---|---|---|---|
| Serum | BN Prospec CardioPhasehsCRP | $y = 0.96 x + 0.03$ mg/L | 0.26 to9.41 | 100 | 0.999 |
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10.5 Specimen Equivalency
The specimen equivalency was determined using the Deming regression model in accordance with CLSI Document EP90c. The following results were obtained:
| SpecimenType | ComparisonAssay (x) | Regression Equation | Sample Range(mg/L) | N | r |
|---|---|---|---|---|---|
| SodiumHeparin | Serum | $y=1.07x - 0.02 \text{ mg/L}$ | 0.22 to 7.40 | 55 | 0.998 |
| PotassiumEDTA | Serum | $y=0.97x - 0.03 \text{ mg/L}$ | 0.22 to 7.40 | 55 | 0.997 |
| LithiumHeparin | Serum | $y=1.07x - 0.03 \text{ mg/L}$ | 0.22 to 7.40 | 55 | 0.998 |
10.6 Interferences
10.6.1 Hemolysis, Icterus, and Lipemia (HIL)
The Atellica CH High Sensitivity C-Reactive Protein 2 assay is designed to have ≤ 10% interference from hemoglobin, bilirubin, and lipemia. Bias is the difference in the results between the control sample (does not contain the interferent) and the test sample (contains the interferent) expressed in a percentage. Bias > 10% is considered interference. Analyte results should not be corrected based on this bias.
Interference testing was performed in accordance with CLSI Document EP07. The following results were obtained:
| Substance | Substance ConcentrationConventional Units (SIUnits)(g/L) | Analyte ConcentrationConventional Units | Bias% |
|---|---|---|---|
| Hemoglobin | 1000 mg/dL (10 g/L) | 0.94 mg/L | 4 |
| 1000 mg/dL (10 g/L) | 2.30 mg/L | 0 | |
| Bilirubin, conjugated | 40 mg/dL (684 $\mu$ mol/L) | 1.10 mg/L | -1 |
| 40 mg/dL (684 $\mu$ mol/L) | 2.80 mg/L | -1 | |
| Bilirubin unconjugated | 40 mg/dL (684 $\mu$ mol/L) | 1.10 mg/L | -1 |
| 40 mg/dL (684 $\mu$ mol/L) | 2.82 mg/L | 0 | |
| Lipemia (Intralipid®) | 3000 mg/dL (30 g/L) | 0.90 mg/L | -7 |
| 3000 mg/dL (30 g/L) | 2.48 mg/L | -4 |
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10.6.2 Non-interfering Substances
The following substances do not interfere with Atellica CH High Sensitivity C-Reactive Protein 2 assay when present in serum and plasma at the concentrations indicated in the table below. Bias due to these substances is ≤ 10%.
Interference testing was performed in accordance with CLSI Document EP07. The following results were obtained:
| Substance | Substance ConcentrationConventional Units | Analyte ConcentrationConventional Units | Bias% |
|---|---|---|---|
| Rheumatoid factors | 500 IU/mL | 0.94mg/L | -1 |
| 500 IU/mL | 2.81mg/L | 0 |
10.6.3 High-Dose Hook Effect / Antigen Excess
High C-reactive protein levels can cause a paradoxical decrease in signal as a result of the high-dose hook effect. In the Atellica CH hCRP2 assay, C-reactive protein levels as high as 1300.00 mg/L will read > 9.50 mg/L.
Clinical Study 11.
Not applicable
11.1 Expected Values
A reference interval for healthy adults was verified in accordance with CLSI Document EP28-A3c.
| Group | Specimen Type | Reference Intervalmg/L |
|---|---|---|
| Low risk for cardiovascular disease prediction | Serum/plasma | < 1.00 |
| Average risk for cardiovascular disease prediction | Serum/plasma | 1.00-3.00 |
| High risk for cardiovascular disease prediction | Serum/plasma | > 3.00 |
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rfai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F; Centers for Disease Control and Prevention Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for heathcare professionals from the Centrol and the American Heart Association. Circulation. 2003 Jan 28;107(3):499-511
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Standardization 12.
The assay is traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference material ERM-DA474/IFCC.
Clinical Cut-off 13.
Not applicable
Conclusion 14.
The results from the performance studies support that the Candidate Device, Atellica CH High Sensitivity C-Reactive Protein 2 assay is substantially equivalent to the Predicate Device, BN ProSpec CardioPhase hsCRP assay (K212559)
§ 866.5270 C-reactive protein immunological test system.
(a)
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.(b)
Classification. Class II (performance standards).