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CardioPhase hsCRP is an in-vitro diagnostic reagent for the quantitative determination of C-reactive protein (CRP) in human serum, and heparin and EDTA plasma by means of particle enhanced immunonephelometry using the BN II and BN ProSpec® System. In acute phase response, increased levels of a number of plasma proteins, including C-reactive protein, is observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurements of hsCRP, 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.

The CardioPhase hsCRP assay is an in-vitro diagnostic reagent for the quantitative determination of Creactive protein (CRP) in human serum, and heparinized and EDTA plasma by means of particleenhanced immunoassay determination. The assay is traceable to the international standard ERM-DA474/IFCC. N Rheumatology Standard SL (cleared under K964527) is used for the establishment of reference curves for the immunonephelometric determination of C-reactive protein on the BN II and BN ProSpec® Systems. This calibrator consists of a mixture of human sera and elevated concentrations of CRP. The CardioPhase hsCRP reagent is a suspension of polystyrene (Latex) particles to which mouse monoclonal anti-human CRP antibodies (< 0.016 g/L) have been attached by covalent bonding. The reagent is a ready-to-use liquid containing preservatives. There are two product variants available. One variant (REF OQIY13) contains 3 x 2 mL vials / box, and the other variant (REF OQIY21) contains 5 x 5 mL vials / box. The assay's 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 relevant protein in the sample. The result is evaluated by comparison with a standard of known concentration.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the method comparison study were that "Results from each lot of CardioPhase hsCRP met the predefined acceptance criteria." While the specific numerical acceptance criteria (e.g., maximum allowable bias) are not explicitly detailed in a table format within the provided text, the successful outcome is stated, and the resulting performance is presented as follows:

2. Sample Sizes Used for the Test Set and Data Provenance

• Sample Size:
  • Lot 1: N = 119
  • Lot 2: N = 116
  • Lot 3: N = 113
  • The total number of samples used in the method comparison study is the sum of these, which is 348.
• Data Provenance: The study was conducted at the "company site in Marburg, Germany." The samples used were "Native serum samples." The text does not explicitly state whether the samples were retrospective or prospective, but the phrasing "Native serum samples were measured" suggests they were existing samples at the time of the study rather than collected specifically for this study.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

This information is not provided in the text. The study describes a method comparison between two quantitative laboratory assays (CardioPhase hsCRP and RCRP Flex reagent cartridge). For this type of in-vitro diagnostic device, the "ground truth" is typically defined by the reference method or the predicate device's measurement, not by human expert consensus or adjudication in the way it might be for image-based diagnostic AI.

4. Adjudication Method for the Test Set

Not applicable for this type of in-vitro diagnostic device and study design. The comparison is quantitative between two analytical methods, not involving human interpretation requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is typically performed for image analysis or other diagnostic tools where human interpretation is a key component. The CardioPhase hsCRP is an in-vitro diagnostic reagent for quantitative measurement, which does not involve human readers in the same way.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, the study described is a standalone performance study of the CardioPhase hsCRP assay compared to a predicate device. It evaluates the device's ability to quantitatively determine C-reactive protein concentrations independently. No human-in-the-loop component is mentioned for the performance evaluation itself.

7. The Type of Ground Truth Used

The "ground truth" for this method comparison study was established by the predicate device, RCRP Flex® reagent cartridge, which runs on the Dimension clinical chemistry system. Both the proposed device (CardioPhase hsCRP) and the predicate device are traceable to the international standard ERM-DA474/IFCC for C-reactive protein measurements. Therefore, the predicate device's measurements serve as the reference for comparison, and that reference itself is traceable to an international standard.

8. The Sample Size for the Training Set

The text does not specify a separate training set or its sample size. The described "method comparison study" is focused on verifying the performance of the device for regulatory submission, using a test set of samples. For in-vitro diagnostic devices, "training sets" are usually relevant for developing the assay itself (e.g., optimizing reagent concentrations, reaction conditions), but this information is not typically detailed in a 510(k) summary with respect to a "training set" of patient data for algorithm development.

9. How the Ground Truth for the Training Set Was Established

As no specific "training set" of patient samples is described in the provided text in the context of algorithm development, this information is not applicable. The assay itself relies on a biochemical principle and calibration traceable to an international standard (ERM-DA474/IFCC), and the calibration is established using N Rheumatology Standard SL, which is traceable to Siemens internal Master Calibrator, which is in turn directly traceable to ERM-DA474/IFCC.

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CardioPhase® hsCRP is an in-vitro diagnostic reagent for the quantitative determination of C-reactive protein (CRP) in human serum, and heparin and EDTA plasma by means of particle enhanced immunonephelometry using the BN II and BN ProSpec® System. In acute phase response, increased levels of plasma proteins, including C-reactive protein, is observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurements of hsCRP, 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.

The CardioPhase hsCRP assay is an in vitro diagnostic reagent for the quantitative determination C-reactive protein, in human serum, and heparinized and EDTA plasma by means of particle-enhanced immunoassay determination. 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 relevant protein in the sample. The result is evaluated by comparison with a standard of known concentration.

This document describes the CardioPhase® hsCRP device, a C-reactive protein immunological test system, and a Special 510(k) submission for a change in its reference standard material from ERM-DA470 to ERM-DA474/IFCC.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state numerical acceptance criteria for all performance characteristics, but rather describes the studies performed and their satisfactory outcomes which imply meeting internal acceptance limits. For instance, for linearity, the stated ranges confirm the measuring range, implying that the observed linearity falls within acceptable deviations. For matrix comparison, high correlation coefficients and slopes close to 1 with intercepts close to 0 indicate acceptable equivalence.

2. Sample Sizes Used for the Test Set and Data Provenance

• Detection Capabilities (LoB, LoD, LoQ):

  • LoB: Five (5) independent analyte-free samples. Conducted with one (1) BN ProSpec System, one (1) BNII System, three (3) different reagent lots, one (1) calibrator lot, five (5) individual aliquots of each sample, and determination on three (3) days. This protocol resulted in 75 measurements per reagent lot, a total of 450 measurements (including the two workflows) on each of the two (2) analyzers, resulting in 900 measurements overall.
  • LoD/LoQ: Serum samples with concentrations ranging from approximately 0.05 mg/L to 0.26 mg/L CRP. Five replicates of six patient samples were run once per day for five days using three hsCRP Reagent lots on one BNProSpec and one BN II, totaling 1080 determinations.
  • Data Provenance: Not explicitly stated (e.g., country of origin). The samples are referred to as "analyte-free" and "patient samples" (serum), implying clinical relevance and likely of human origin. The study appears to be prospective as it was specifically designed for this evaluation.

• Linearity:

  • Sample Size: A high CRP serum pool was mixed with a low serum pool to generate 13 concentrations. Each level was tested in four-fold determination.
  • Data Provenance: Not explicitly stated (e.g., country of origin). The samples are described as "serum pool," implying human origin. The study appears to be prospective.

• Method Comparison:

  • Sample Size: Native samples in the range of 0.27 and 11.90 mg/L for CRP2 and native samples in the range of 3.87 and 61.40 mg/L for CRP1. The exact number of samples is not explicitly given, but it implies a sufficient number to perform linear regression and bias calculations across the specified ranges.
  • Data Provenance: Not explicitly stated (e.g., country of origin). Native samples imply human origin. The study appears to be prospective for this comparison.

• Matrix Comparison:

  • Sample Size: For each sample type (EDTA plasma and lithium heparin plasma compared to serum), a total of 60 native samples spanning the measuring range were evaluated.
  • Data Provenance: Not explicitly stated (e.g., country of origin). Native samples imply human origin. The study appears to be prospective.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

For this in-vitro diagnostic device (quantitative determination of C-reactive protein), "ground truth" is typically established by reference methods or gravimetrically prepared standards with known concentrations, or by comparison to a reference standard material.

• Traceability and Standardization: The ground truth for this device is primarily established by its traceability to the IFCC European Reference Material ERM-DA474/IFCC, which is "certified for C-reactive protein measurements." This reference material serves as the "expert" or definitive standard.
• No human expert panel for ground truth: Unlike image-based diagnostic devices, this type of immunoassay does not involve human experts establishing a "ground truth" based on interpretations (e.g., radiologists labeling images). The "ground truth" is analytical and defined by international reference standards.

4. Adjudication Method for the Test Set

Not applicable in the conventional sense. For an in-vitro diagnostic assay that measures a quantitative analyte, the "ground truth" is the certified value assigned to reference materials or the result from a highly accurate reference method. There is no subjective interpretation by multiple human adjudicators in the way there would be for an imaging diagnosis.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No. This is an in-vitro diagnostic (IVD) device for quantitative measurement of a biomarker (CRP). MRMC studies are typically performed for devices that involve human interpretation, such as imaging AI applications, to assess how AI assistance impacts human reader performance. This device does not have a "human reader" component in that context.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, entirely. The entire performance evaluation (detection capabilities, linearity, method comparison, matrix comparison) demonstrates the standalone performance of the CardioPhase® hsCRP assay system (reagent and instrument) in measuring CRP levels. The device itself, once calibrated, provides a quantitative result without human-in-the-loop performance influencing the measurement. The human role is in operating the instrument and interpreting the numerical result in a clinical context, but not in directly influencing the measurement itself.

7. Type of Ground Truth Used

The ground truth used is primarily certified reference materials (ERM-DA474/IFCC) and comparative analysis against a previously cleared predicate device (which itself was traceable to ERM-DA470) which acts as a well-established reference. The "ground truth" for the calibrator N Rheumatology Standard SL is its traceability to the Siemens internal Master Calibrator, which in turn is directly traceable to ERM-DA474/IFCC.

8. Sample Size for the Training Set

Not applicable. This document describes the performance evaluation of a change to an existing in-vitro diagnostic reagent and its calibrator. This is not a machine learning or AI-based device that typically requires a "training set" in the context of model development. The characterization studies described are for analytical performance verification of the assay system, rather than training a computational algorithm.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no "training set" for this type of IVD device.

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