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K-ASSAY® CRP (Ver.2) is intended to be used for the quantitative determination of C-reactive protein (CRP) in human serum and plasma (potassium-EDTA or lithium-heparin) by immunoturbidimetric assay. Measurement of CRP aids in the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. FOR IN VITRO DIAGNOSTIC USE.

The K-ASSAY® CRP (Ver.2) assay quantifies C-reactive protein based on immunoturbidimetric assay. The reagent uses latex combined with goat polyclonal antibody specific to human CRP. By adsorbing CRP in the sample to the surface of the latex particles and reacting it with the anti-CRP antibody, specific aggregation corresponding to the CRP concentration occurs. Since the absorbance of the reaction changes in proportion to the amount of aggregation, the concentration of CRP in the sample is determined based on the calibration curve prepared using a standard of known CRP concentrations. The K-ASSAY® CRP (Ver.2) assay can be run using a chemistry analyzer. 6 levels of calibrators from the K-ASSAY® CRP Calibrator (Ver.2) calibrators are used for quantifying the levels of CRP present in the patient's sample.

This document describes the FDA 510(k) clearance for the K-ASSAY CRP (Ver.2) IVD device. This device is an in-vitro diagnostic test system, which means it analyzes biological samples in a lab setting rather than directly interacting with a patient.

Therefore, the concepts of "human readers," "AI assistance," "effect size," "multi reader multi case (MRMC) comparative effectiveness study," and "standalone (i.e. algorithm only without human-in-the loop performance)" are not applicable in this context. These terms are typically used for medical imaging AI/ML devices where human interpretation is involved.

For this in-vitro diagnostic device, the "acceptance criteria" and "study that proves the device meets the acceptance criteria" are related to its analytical performance characteristics when compared to a predicate device, and the reported device performance refers to the results of these analytical studies.

Here's the breakdown of the information provided within the scope of this IVD device:

1. Table of Acceptance Criteria and Reported Device Performance

For an IVD device like the K-ASSAY® CRP (Ver.2), the acceptance criteria are generally established by demonstrating equivalent or superior analytical performance compared to a legally marketed predicate device, and meeting established CLSI guidelines for accuracy, precision, linearity, and interference. The "reported device performance" refers to the actual study results for these characteristics.

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

• Method Comparison: n = 175 clinical native serum samples.
• Linearity: The number of samples/dilutions used is not explicitly stated, but the tested range was 4.6 - 441.2 mg/L.
• Limit of Quantitation (LoQ): Not specified in terms of sample size for the LoQ determination itself (typically involves low-concentration samples measured multiple times).
• Matrix Comparison: 42 donor samples (each collected into 3 different tubes: serum, K2-EDTA plasma, Li-Heparin plasma).
• Precision (Single-site): For each of the 7 samples/controls, N=240 individual measurements (2 runs/day x 2 replicates/run x 20 days x 3 lots).
• Precision (Multisite): For each of the 7 samples/controls, N=75 individual measurements (1 run/day x 5 replicates/run x 5 days x 3 analyzers).
• Interference: The number of unique samples tested for interference is not explicitly stated. Typically, a few samples (e.g., low, medium, high concentration) are spiked with interferents and compared to unspiked controls.
• Expected Values: 168 normal serum samples.
• Data Provenance: The document states for "Expected Values" that 168 normal serum samples were "taken from healthy individuals in the U.S." This indicates a U.S. origin for at least this specific study. For other studies (Method Comparison, Precision, Linearity, Interference, Matrix Comparison), the specific country of origin is not mentioned. All studies are retrospectively analyzed in the sense that they were completed performance validation studies submitted to FDA.

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

For an in-vitro diagnostic device like this CRP assay, the "ground truth" is established through highly accurate and precise reference methods or established predicate devices, adhering to rigorous analytical chemistry best practices and guidelines (e.g., CLSI standards). There isn't a panel of human "experts" like radiologists interpreting images. The "ground truth" is quantitative and objective, derived from reference measurements.

In this case:

• Method Comparison: The predicate device (K-ASSAY® CRP (3), K023828) serves as the comparator for method comparison, which represents the established "ground truth" for clinical samples.
• Linearity, LoQ, Precision, Interference, Matrix Comparison: The "ground truth" for these analytical performance studies is established by rigorous laboratory protocols, highly calibrated equipment, reference materials, and adherence to CLSI guidelines. The performance is assessed against predefined statistical criteria rather than expert consensus on individual cases.
• Expected Values: The ground truth comes from established clinical literature and verified normal ranges based on studies of healthy populations.

4. Adjudication Method for the Test Set

Not applicable for an IVD device. Adjudication methods (e.g., 2+1, 3+1) are used in studies where subjective human interpretation (e.g., image reading) requires consensus building for ground truth establishment. For quantitative IVD assays, the results are numerical and objectively measured; therefore, there's no need for adjudication.

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

No. As explained above, this is an in-vitro diagnostic device, not an imaging AI/ML device involving human readers.

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

Yes, in essence, all the analytical performance studies (Method Comparison, Linearity, LoQ, Precision, Interference, Matrix Comparison) are "standalone" in nature for an IVD. The device's performance is evaluated based solely on its ability to accurately and precisely measure CRP concentrations in samples, without any human interpretation of the measurement itself or the involvement of an "algorithm" in the AI/ML sense. The device directly processes the sample and outputs a quantitative result.

7. The Type of Ground Truth Used

The ground truth for this IVD device's performance studies is primarily based on:

• Reference Method/Predicate Device Comparison: For the method comparison study, the predicate device serves as the reference against which the new device's measurements are compared.
• Reference Materials and Calibrators: For linearity, LoQ, and precision studies, the ground truth for concentration values is established using certified reference materials and meticulously prepared calibrators with known concentrations.
• Spiked Samples: For interference studies, known amounts of interfering substances are added to samples, and the true CRP concentration (before interference) serves as the baseline ground truth.
• Clinical Literature/Established Norms: For "Expected Values," the ground truth is derived from widely accepted clinical ranges and population studies cited in the literature.

8. The Sample Size for the Training Set

This document describes a 510(k) submission for a traditional IVD device, not an AI/ML-based device. Therefore, there is no "training set" in the context of machine learning. The device's performance is based on its chemical and physical principles (latex-enhanced immunoturbidimetric assay) and validated through the analytical studies detailed.

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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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:

• 1. For serum/plasma, dispenses 30 µL of primary sample and 90 µL of Atellica CH Diluent into a dilution cuvette.
• 2. Dispenses 100 µL of Reagent 1 into a reaction cuvette.
• 3. Dispenses 3 µL of pre-diluted sample into a reaction cuvette.
• 4. Dispenses 45 µL of Reagent 2 into a reaction cuvette.
• 5. Mixes and incubates the mixture at 37°C.
• 6. Measures the absorbance after Reagent 2 addition.
• 7. 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:

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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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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The Beckman Coulter DxC 500 AU Clinical Chemistry Analyzer is an automated chemistry analyzer that measures analytes in samples, in combination with appropriate reagents, calibrators, quality control (QC) material and other accessories. This system is for in vitro diagnostic use only.

The Glucose test system is for the quantitative measurement of glucose in human serum, plasma, urine and cerebrospinal fluid on Beckman Coulter AU/DxC AU analyzers. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and of pancreatic islet cell carcinoma.

System reagent for the quantitative determination of C-Reactive Protein in human serum and plasma on Beckman Coulter AU/DxC AU Analyzers. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. Measurements may also be useful 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. Reagents for the quantitative determination of Sodium, Potassium and Chloride concentrations in human serum, plasma and urine on the Beckman Coulter ISE modules.

The sodium test system is intended for the quantitative measurement of sodium in serum, plasma, and urine.

Measurements obtained by this device are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

The potassium test system is intended for the quantitative measurement of potassium in serum, plasma, and urine. Measurements obtained by this device are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels.

The chloride test system is intended for the quantitative measurement of the level of chloride in plasma, serum, and urine. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis.

The Beckman Coulter DxC 500 AU Clinical Chemistry Analyzer carries out automated analysis of serum, plasma, urine samples and other body fluids and automatically generates results. The device is an automated photometric clinical analyzer that measures analytes in samples, in combination with appropriate reagents, calibrators, quality control (QC) material and other accessories. This system is for in vitro diagnostic use only. Electrolyte measurement is performed using a single cell lon Selective Electrode (ISE) which is also common among the other members of the AU family.

The ISE module for Na+, K+, and Cl- employs crown ether membrane electrodes for sodium and potassium and a molecular oriented PVC membrane for chloride that are specific for each ion of interest in the sample. An electrical potential is developed according to the Nernst Equation for a specific ion. When compared to the Internal Reference Solution, this electrical potential is translated into voltage and then into the ion concentration of the sample.

In this Beckman Coulter procedure, glucose is phosphorylated by hexokinase (HK) in the presence of adenosine triphosphate (ATP) and magnesium ions to produce glucose-6-phosphate (G-6-P) and adenosine diphosphate (ADP). Glucose-6phosphate dehydrogenase (G6P-DH) specifically oxidizes G-6-P to 6phosphogluconate with the concurrent reduction of nicotinamide adenine dinucleotide (NAD+) to nicotinamide adenine dinucleotide, reduced (NADH). The change in absorbance at 340/660 nm is proportional to the amount of glucose present in the sample.

The CRP Latex reagent is an in vitro diagnostic device that consists of ready to use buffer and latex particles coated with rabbit anti-CRP antibodies. In this procedure, the measurement of the rate of decrease in light intensity transmitted through particles suspended in solution is the result of complexes formed during the immunological reaction between the CRP of the patient serum and rabbit anti-CRPantibodies coated on latex particles. Two measuring range settings are available: Normal application (CRP Concentrations ranging between 5.0-480 mg/L) and Highly Sensitive (Cardiac) Application- (CRP concentrations ranging between 0.2-80mg/L).

This document describes the acceptance criteria and supporting study for the Beckman Coulter DxC 500 AU Clinical Chemistry Analyzer and its associated reagents (Glucose, CRP Latex, ISE Reagents for Sodium, Potassium, and Chloride).

1. Table of Acceptance Criteria and Reported Device Performance

The device performance was evaluated across several metrics. The table below summarizes the acceptance criteria (often implied by the "Pass" result and the specific targets within the CLSI guidelines references) and the reported performance for key tests:

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

The studies used various sample sizes for different tests, primarily patient samples and prepared sample pools. The provenance of the data is not explicitly stated in terms of country of origin, but it is implied to be clinical laboratory data. The studies are non-clinical (bench) studies following CLSI protocols, which suggests they were conducted in a controlled laboratory environment. The data is retrospective in the sense that it relies on established methods and samples to evaluate the new device against a predicate.

• Method Comparison:

  • hsCRP (Cardiac): 115 serum samples
  • CRP Normal: 120 serum samples
  • Glucose (Serum): 133 serum samples
  • Glucose (Urine): 113 urine samples
  • Glucose (CSF): 111 CSF samples
  • ISE Sodium (Serum): 120 serum samples
  • ISE Potassium (Serum): 119 serum samples
  • ISE Chloride (Serum): 120 serum samples
  • ISE Sodium (Urine): 117 urine samples
  • ISE Potassium (Urine): 120 urine samples
  • ISE Chloride (Urine): 114 urine samples

• Linearity/Reportable Range: High and low sample pools were prepared and inter-diluted. Test samples were assayed in quadruplicate. The total number of unique samples is not specified, but multiple dilutions were tested.

• Sensitivity (Detection Limits): Replicate measurements on blank and low-level samples across multiple days using multiple reagent lots. The specific number of samples is not detailed, but the method suggests an adequate number of replicates for statistical determination.

• Precision/Reproducibility: Duplicate sample analysis, twice daily, over 20 days (n=80) for multiple sample levels (typically 3-5 levels per test).

• Interferences: 5 replicates of test samples at two analyte levels.

• Reference Interval: At least 20 reference individuals (e.g., 25 for CRP Latex Serum, 23 for Glucose Serum, 24 for Glucose Urine, 20 for ISE Serum tests).

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

This submission is for an in vitro diagnostic (IVD) device, specifically a clinical chemistry analyzer and its reagents. For such devices, "ground truth" is typically established by comparing the device's results to established, legally marketed predicate devices and reference methods, as well as adherence to recognized industry standards (CLSI guidelines).

• Experts: The document does not describe the use of human experts to establish "ground truth" in the way it might for an AI-powered image analysis device (e.g., radiologists). Instead, the "ground truth" for the test set values themselves is derived from the established analytical performance of the predicate device and the reference methods outlined in the CLSI guidelines.
• Qualifications: The "experts" in this context would be the skilled laboratory personnel performing the CLSI guideline-based studies and the manufacturers establishing the performance claims for both the candidate and predicate devices. Their qualifications align with standard laboratory practices and regulatory requirements for IVD development and validation.

4. Adjudication Method for the Test Set

No explicit adjudication method (like 2+1 or 3+1 consensus) is described, as this would typically apply to subjective interpretations (e.g., image reading by multiple human experts). For an IVD device measuring analytes, the evaluation is based on quantitative data comparison against established reference methods and performance specifications, using statistical analysis. The "pass" criteria for each test inherently serve as the "adjudication" against the set performance targets.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Reader Improvement with AI vs. Without AI Assistance

No MRMC study was done, nor is it applicable. This submission is for an automated clinical chemistry analyzer and its reagents, which quantitatively measure analytes. It is not an AI-assisted diagnostic imaging or interpretation device that clinicians would use to read cases or images. Therefore, there is no human-in-the-loop component for which an AI assistance effect size would be relevant.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the studies presented are essentially standalone performance evaluations of the DxC 500 AU Clinical Chemistry Analyzer and its associated reagents. The "algorithm" here refers to the instrument's automated analytical processes (photometric, ISE, etc.) and the reagent chemistries. The performance data (method comparison, linearity, precision, sensitivity, interference) directly reflects the device's analytical capability without direct human interpretation or intervention in the measurement process itself, beyond sample preparation and loading. Human oversight is involved in quality control and interpretation of results, but the core analytical performance is standalone.

7. The Type of Ground Truth Used

The ground truth for evaluating the device's performance is primarily established through:

• Comparison to Predicate Device: The DxC 700 AU Clinical Chemistry Analyzer (K161837), which is a legally marketed device with established performance.
• CLSI Guidelines: Standardized laboratory protocols (e.g., EP09C-ED3 for Method Comparison, EP06-ED2 for Linearity, EP17-A2 for Sensitivity, EP05-A3 for Precision) that define acceptable analytical performance.
• Established Reference Ranges: For reference interval studies, existing medical literature or established clinical laboratory reference intervals are used, with verification that a high percentage of samples fall within these ranges on the new device.
• Spiked Samples and Known Concentrations: For linearity, sensitivity, and interference studies, samples are engineered with known concentrations of analytes and/or interferents to challenge the device across its claimed range and conditions.

8. The Sample Size for the Training Set

This type of product (clinical chemistry analyzer and reagents) does not typically involve a "training set" in the context of machine learning or AI models. The development process for such devices relies on chemical and engineering principles, followed by rigorous analytical validation (the studies described above). Therefore, a "training set" size is not applicable.

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

As explained above, there is no "training set" for this type of medical device. The "ground truth" and performance establishment for the device's design and analytical methods would be rooted in fundamental scientific knowledge of chemistry, reagent interactions, and photometric/electrochemical detection, corroborated by extensive internal development and testing against established analytical standards and predicate devices.

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The C-Reactive Protein Extended Range (RCRP) method used on the Dimension® clinical chemistry system is an in vitro diagnostic test intended for the quantitative determination of CRP in human serum and plasma (lithium heparin). Measurement of C-Reactive Protein is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases.

The RCRP method is based on a particle enhanced turbidimetric immunoassay (PETIA) technique. Synthetic particles coated with antibody to C-Reactive Protein (AbPR) aggregate in the presence of C-Reactive Protein in the sample. The increase in turbidity which accompanies aggregation is proportional to the C-Reactive Protein concentration.

This document describes the RCRP Flex® reagent cartridge, an in vitro diagnostic test for the quantitative determination of C-Reactive Protein (CRP) in human serum and plasma. The submission is a special 510(k) for a modified device, primarily due to an update in traceability from IFCC CRM 470 to ERM-DA474/IFCC reference material and a change in the analytical measurement range (AMR).

Here's an analysis of the acceptance criteria and study data based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria and observed performance are provided for the method comparison studies.

Detection Capability (LoB, LoD, LoQ)

Interference

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

• Method Comparison – Modified RCRP assay vs Predicate RCRP assay:

  • Sample Size: 132 individual human native serum samples.
  • Data Provenance: Samples were obtained from "specimen vendors". The country of origin is not specified, nor is whether the data is retrospective or prospective.

• Method Comparison - RCRP assay on Dimension RXL system vs N High Sensitivity CRP on the BN™ System:

  • Sample Size: 171 for the overall comparison (5.3 to 241.3 mg/L) and 39 for the narrower range (5.3 to 20.2 mg/L).
  • Data Provenance: This study involved "re-analyzed historical IFU data." The original provenance (country, retrospective/prospective) of this historical data is not specified.

• Linearity Testing: Not specified, but generally involves a set of diluted samples or spiked matrix covering the analytical measurement range.

• Detection Capability (LoB, LoD, LoQ): Not specified.

• Precision:

  • Sample Size: 6 serum samples, analyzed with N=10 replicates each day for 5 days (total of 50 replicates per sample level).

• Specimen Equivalency:

  • Sample Size: 73 samples.
  • Data Provenance: Not specified, but likely from specimen vendors similar to the method comparison.

• Interference:

  • Sample Size: Not explicitly stated, but typically involves a control sample and test samples (with interferent) for assessment of bias.

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

This document describes an in vitro diagnostic (IVD) test, specifically an immunoassay for C-Reactive Protein. The "ground truth" for such devices is typically established through a reference method or known concentrations of certified reference materials, not through expert consensus or interpretation in the same way an imaging AI might.

• No human experts (e.g., radiologists) were used to establish ground truth for this type of device. The assessment is based on measured concentrations against established reference standards.

4. Adjudication Method for the Test Set

Not applicable. As described above, the ground truth for an IVD device like this is based on quantitative measurements and reference materials, not subjective interpretations requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is an in vitro diagnostic assay, not an AI-powered image analysis or diagnostic assist device that would involve human readers.

6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done

This device is a standalone algorithm/reagent system designed for automated quantitative measurement on a clinical chemistry system. Its performance is evaluated intrinsically through various analytical studies (method comparison, linearity, precision, detection capability, interference) without human-in-the-loop performance influencing the measurement itself. The results are then interpreted by clinicians.

7. The Type of Ground Truth Used

The ground truth for this device is based on:

• Reference Materials: For standardization, the device is traceable to ERM-DA474/IFCC reference material (and previously IFCC CRM 470). These are internationally recognized certified reference materials for CRP.
• Comparative Methods: The performance is benchmarked against a predicate RCRP assay and the N High Sensitivity CRP on the BN™ System. These are established laboratory methods.
• Clinical Laboratory Standards (CLSI): The studies follow guidelines from CLSI, which define how to robustly evaluate analytical performance parameters like precision, linearity, and detection limits.

8. The Sample Size for the Training Set

This document does not describe a machine learning or AI model that requires a distinct "training set" in the conventional sense. The device is a chemical reagent and assay system. Its "training" or development would involve extensive experimentation and optimization during the R&D phase to ensure reagent stability, reaction kinetics, and signal transduction are robust and accurate. This is not typically quantified as a "training set size" like in AI/ML contexts.

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

Not applicable, as this is not an AI/ML device with a defined training set and ground truth in that context. The "ground truth" for the development of such an assay would be through rigorous chemical and biological characterization, using known concentrations of analytes, reference materials, and established analytical chemistry principles.

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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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The Procise CRP assay is a time-resolved fluorescence energy transfer immunoassay for the quantitative determination of C-Reactive Protein (CRP) levels in human serum. The test is carried out by means of the ProciseDx Analyzer.

Measurement of CRP aids in evaluation of injury to body tissues, inflammatory disorders. The instrument and assay are for use by trained professionals in the clinical laboratory. For in vitro diagnostic use only. Not for point of care use.

The Procise CRP assay is a homogeneous sandwich immunoassay assay that uses a fluorescence resonance energy transfer (FRET) signal to detect and quantify CRP. FRET is a process in which a donor molecule, in an excited state, transfers excitation energy to an acceptor fluorophore when the two are brought into close proximity. Upon excitation at a characteristic wavelength the energy absorbed by the donor is transferred to the acceptor, which in turn emits light energy. The level of light emitted from the acceptor fluorophore is directly proportional to the degree of donor/acceptor complex formation.

The Procise CRP assay format is designed as a competitive format. A monoclonal anti-CRP antibody and exogenous CRP antigen are labeled with donor and acceptor fluorophores, respectively. The monoclonal antibody specific for CRP is labelled with the donor fluorophores and the CRP antigen is labelled with the acceptor fluorophore. Similar to other competitive assay formats, as the concentration of CRP increases a proportional decrease in the signal is observed.

The Procise CRP Assay Kit, ProciseDx Instrument, and ProciseDx Calibration Cartridge (K201256) is a device for the quantitative determination of C-Reactive Protein (CRP) levels in human serum. It is intended to aid in the evaluation of injury to body tissues, infection, and inflammatory disorders.

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

1. Table of Acceptance Criteria and Reported Device Performance

The FDA clearance document does not explicitly state "acceptance criteria" in a quantified table for all performance characteristics. Instead, it presents the results of individual studies and implicitly expects them to demonstrate substantial equivalence to the predicate device and meet typical analytical performance standards for in vitro diagnostic devices. Below is a summary of the performance characteristics obtained from the studies. For qualitative criteria like specificity, "No significant interference" serves as the reported performance, implying it met an internal acceptance threshold. For quantitative metrics like precision, the reported values are the performance.

Detailed Study Information:

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

• Precision (Within-Laboratory): 6 serum samples tested; 160 test results generated per sample (2 replicates x 2 runs x 20 days x 2 lots). Data provenance is not explicitly stated (e.g., country of origin, retrospective/prospective), but the study design suggests controlled laboratory experiments, likely prospective.
• Precision (Between-site): 5 serum samples (3 patients, 2 QCs) tested; 180 determinations per sample (3 replicates x 2 runs x 5 days x 2 instruments x 3 sites). Data provenance is not explicitly stated (e.g., country of origin), but the multi-site nature suggests controlled laboratory experiments, likely prospective.
• Linearity: 11 dilution levels of pooled human serum samples (range 3.6 to 161.0 mg/L CRP). Each dilution measured in 3 or 4 replicates. Data provenance not explicitly stated, likely laboratory-prepared samples.
• Analytical Specificity/Interference: 3 pooled human serum samples with varying CRP concentrations (12.3, 52.9, and 89.7 mg/L). Each sample spiked with interferents and measured in 3 replicates. Data provenance not explicitly stated, likely laboratory-prepared samples.
• Accuracy (Instrument): 11 dilution levels (1.0 to 41.2 mg/L CRP) of ERM® -DA474/IFCC serially diluted with CRP-depleted human serum. Each diluted sample tested in 3 replicates, original ERM® -DA474/IFCC tested in 6 replicates. Data provenance not explicitly stated, likely laboratory-prepared samples.
• Detection Limits (LoB, LoD, LoQ):
  • LoB: 4 analyte-depleted serum samples. Each tested in 5 replicates per run, 1 run per day for 3 days (total 60 measurements per reagent lot).
  • LoD: 5 low-level serum samples. Each tested in 4 replicates per run, 1 run per day for 3 days (total 60 measurements per reagent lot).
  • LoQ: 5 low measurand content serum samples. Each tested in 4 replicates per run, 1 run per day for 3 days (total 24 measurements).
    Data provenance for these serum samples is not explicitly stated, but they are likely from human sources (e.g., blood banks, clinical labs), and the testing is prospective.
• Method Comparison with Predicate Device: 81 serum samples spanning the assay measuring interval (5.3 - 134.0 mg/L). Data provenance is not explicitly stated, but these are patient samples, likely collected retrospectively or prospectively from a clinical setting.
• Expected Values/Reference Range: 170 samples (88 male, 82 female) from normal healthy subjects. Data provenance is not explicitly stated, but these are human subjects, likely collected prospectively.

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

The device is an in vitro diagnostic (IVD) assay for measuring a biomarker (CRP). For such devices, "ground truth" is typically established by reference methods, certified reference materials, or values obtained from a predicate device, rather than expert consensus on images or clinical cases.

• For Accuracy/Traceability: The ground truth for CRP concentration was established using ERM® -DA474/IFCC, which is a certified reference material. This does not involve human experts establishing ground truth in the traditional sense of medical image interpretation.
• For Method Comparison: The predicate device, Orion Diagnostica QuikRead go CRP (K142993), serves as the reference for comparison, effectively establishing the comparative "ground truth" for the new device's performance.

Therefore, the concept of "number of experts" and "qualifications of those experts" as it might apply to image-based AI studies is not directly applicable here.

4. Adjudication Method for the Test Set:

Adjudication methods (like 2+1, 3+1) are typically used in studies involving subjective assessment (e.g., by radiologists interpreting images) to resolve discrepancies among experts. Since this device measures a quantitative biomarker and uses reference methods or a predicate device for comparison, there is no human adjudication process involved in establishing the "ground truth" values for the test samples. The values are either inherent to the reference material or determined by the predicate method.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

No. An MRMC comparative effectiveness study is not applicable as this is an in vitro diagnostic (IVD) device for quantitative measurement of a biomarker, not a device that involves human interpretation of images or other qualitative data, nor is it an AI-assisted diagnostic tool for human readers. Therefore, there is no "human readers improve with AI vs without AI assistance" to report.

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

Yes, the studies presented are all standalone performance evaluations of the device (Procise CRP assay on the ProciseDx Analyzer). This is a laboratory-based automated assay that measures CRP concentration directly. Its performance is evaluated purely based on its analytical output against known standards or predicate methods, without human interpretation as part of the measurement process itself. While trained professionals are required to use the instrument, the performance characteristics reported (precision, linearity, accuracy, etc.) are solely attributable to the device's measurement capabilities.

7. The Type of Ground Truth Used:

The ground truth used for the studies includes:

• Certified Reference Materials: ERM® -DA474/IFCC for traceability and instrument accuracy.
• Predicate Device Measurements: Measurements from the Orion Diagnostica QuikRead go® CRP device for method comparison.
• Prepared Samples with Known Concentrations: For linearity, interference, and stability studies, samples were either serially diluted from known concentrations or pooled and spiked to achieve specific, known levels.
• Clinically Characterized Samples: For the reference range study, samples were from "normal healthy subjects" with specific exclusion criteria (e.g., obesity), but the CRP levels themselves were determined by the device, establishing a reference interval rather than confirming a specific pre-defined "ground truth" for each individual sample's CRP value.

8. The Sample Size for the Training Set:

The document does not specify a separate "training set" in the context of machine learning or AI. This device is an immunoassay, not an AI-driven prediction model. Therefore, the concept of a training set as understood in AI development is not directly applicable. The "training" of the assay is its inherent chemical and optical design, and its calibration is based on reference materials.

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

Again, the concept of a "training set" and associated ground truth establishment is not relevant for this type of immunoassay device. The device's operational parameters and calibration are established through laboratory experiments using certified reference materials and established analytical methods, not through a machine learning training process with a specific "training set" and corresponding ground truth labels.

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Yumizen C1200 CRP reagent is intended for the quantitative in vitro diagnostic determination of the C-reactive protein in human serum and lithium heparin plased on an immunoturbidimetric assay. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues and for evaluation of infections, tissue injury and inflammatory disorders. This test should be used in conjunction with other laboratory and clinical findings.

Yumizen C1200 CRP (Licensed for USP6, 248, 597/ USP6, 828, 158 and equivalent patents in other countries) is a latex-enhanced immunoturbidimetric assay developed to accurately measure CRP levels in serum and plasma samples for conventional CRP ranges.

When an antigen-antibody reaction occurs between CRP in a sample and anti-CRP antibody which has been sensitized to latex particles, agglutination results. This agglutination is detected as an absorbance change, with the magnitude of the change being proportional to the quantity of CRP in the sample. The actual concentration is then determined by interpolation from a calibration curve prepared from calibrators of known concentration.

Reagents Yumizen C1200 CRP is ready-to-use.

Reagent 1: Buffer solution: Glycine buffer solution Reagent 2: Latex suspension: 0.20% w/v suspension of latex particles sensitized with anti-CRP antibodies (rabbit)

After measurements are taken, reagent cassettes should remain in the refrigerated tray.

Care should be taken not to interchange the caps with others cassettes.

Reagents with different lot numbers should not be interchanged or mixed.

This submission consists of the Yumizen C1200 CRP (1300023877) reagent for serum and plasma testing for Yumizen C1200 reagent CRP, the submission includes the controls Yumizen C1200 Level 1 Protein Control (1300023944) and Yumizen C1200 Level 2 Protein Control (1300023945) for use on Yumizen C1200 Analyzer. The submission for Yumizen C1200 reagent CRP also includes the corresponding calibrator Yumizen C1200 CRP Cal (1300023899) for use on Yumizen C1200 Analyzer.

The acceptance criteria and study proving the device meets them are detailed below for the Yumizen C1200 CRP reagent.

1. A table of acceptance criteria and the reported device performance

2. Sample size used for the test set and the data provenance

• Limit of Quantitation (LOQ): Five samples were used, assayed over five days, with two runs of four replicates per sample per day (for each reagent lot). These samples came from diluting individual serum samples by commercial depleted serum.
• Linearity: Each level of a range of samples (covering 9.42 to 150.78 mg/L) was assayed 3 times. The highest concentration sample was pooled human sera spiked with CRP stock solution.
• Total Precision (20x2x2):
  • Sample Size: 240 measurements per sample/control (20 days * 2 series/day * 2 replicates/series * 3 analyzers * 3 reagent lots, assuming pooling of data) for 5 specimens (pooled human sera) and 2 controls (Yumizen C1200 Level 1 and 2 Protein Control).
  • Provenance: Pooled human sera were anonymous remnants of human sera specimens collected from routine clinical laboratory.
• Instrument Variability (3x5x2x3):
  • Sample Size: 90 measurements per sample/control (3 instruments * 5 days * 2 series/day * 3 replicates/series) for 6 samples (pooled human sera) and 2 controls (Yumizen C1200 Level 1 and 2 Protein Control).
  • Provenance: Pooled human sera were anonymous remnants of human sera specimens collected from routine clinical laboratory.
• Lot to Lot Variability (3x5x2x3):
  • Sample Size: 90 measurements per sample/control (3 reagent lots * 5 days * 2 series/day * 3 replicates/series) for 6 samples (pooled human sera) and 2 controls (Yumizen C1200 Level 1 and 2 Protein Control).
  • Provenance: Pooled human sera were anonymous remnants of human sera specimens collected from routine clinical laboratory.
• Interferences: Pooled Human sera were used. Substances were added to base sera at two different CRP concentrations (normal and high).
• Exogenous Interferences (Matrix Comparison): 38 paired samples (sera and heparinized plasma) from individual donors from a blood bank were evaluated. Only native samples were used.
• Method Comparison: 102 native samples were used, assayed in duplicate. These samples were anonymous remnants of human serum specimens collected from routine clinical laboratory.
• Reference Range: 80 "normal samples" from a blood bank were assayed in duplicates.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

This information is not provided in the given text. For an in vitro diagnostic device like the Yumizen C1200 CRP, the "ground truth" for quantitative measurements is typically established through reference methods or established calibrators, not through expert consensus in the same way an imaging AI algorithm's ground truth might be. The reference ranges are verified against literature, not established by experts for the study itself.

4. Adjudication method for the test set

This information is not applicable for this type of in vitro diagnostic device study. Adjudication methods like 2+1 or 3+1 are typically used for establishing ground truth in studies involving human interpretation (e.g., radiology reads for an AI algorithm), not for quantitative analytical performance studies of a laboratory instrument and reagent.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This information is not applicable as this is an in vitro diagnostic device for C-reactive protein (CRP) measurement, not an AI-assisted diagnostic tool that involves human readers/interpreters.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

This is a standalone diagnostic system (instrument + reagent) for measuring CRP. Its performance is entirely "algorithm only" in the sense that the instrument provides a quantitative result without human-in-the-loop interpretation of raw data, beyond operating the instrument and interpreting the numerical output. The studies detailed (linearity, precision, interference, method comparison) are all evaluating this standalone performance.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The "ground truth" for the performance characteristic studies of the Yumizen C1200 CRP reagent is established through:

• Reference methods and calibrators: For accuracy and linearity, performance is assessed against known concentrations or calibrated materials (e.g., using ERM-DA 474 or IRMM/ERM-DA472/IFCC for traceability).
• Statistical analysis: Precision measurements rely on statistical reproducibility.
• Comparative methods: Method comparison studies compare the device's results to a legally marketed comparator device (BECKMAN COULTER CRP reagent model: CRP LATEX REAGENT OSR6199 on Olympus AU400).
• Reference literature: The reference range for CRP is verified against established scientific literature.

8. The sample size for the training set

This information is not applicable as this is an in vitro diagnostic device, not a machine learning or AI model that requires a "training set." The development of the reagent and instrument might involve internal optimization, but it's not described in terms of a formal "training set" like an AI model.

9. How the ground truth for the training set was established

This information is not applicable for the reasons stated in point 8.

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Tina-quant® C-Reactive Protein IV is an immunoturbidimetric assay for the in vitro quantitative determination of CRP in human serum and plasma on cobas c systems.

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 plasma. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.

The Tina-quant® C-Reactive Protein IV reagent will be a liquid ready to use 2 component particle enhanced immunoturbidimetric assay.

Reagents - working solutions

R1: TRIS* buffer with bovine serum albumin; preservatives

R2 Latex particles coated with anti-CRP (mouse) in glycine buffer; immunoglobulins (mouse); preservative

• TRIS= Tris(hydroxymethyl)-aminomethane

The Tina-quant® C-Reactive Protein IV assay will be based on the DUREL technology (dual radius enhanced latex - technology) which is also used in C-Reactive Protein Gen.3 predicate method. Human CRP agglutinates with latex particles coated with monoclonal anti-CRP antibodies. The aggregates are determined turbidimetrically.

The document describes the non-clinical performance evaluation of the Tina-quant® C-Reactive Protein IV device. Here's a summary of the acceptance criteria and the study that proves the device meets them:

1. A table of acceptance criteria and the reported device performance

Study Details:

The performance studies were designed in accordance with CLSI guidelines (EP5-A3, EP17-A2, EP6-A) and FDA guidance for CRP assays.

2. Sample sized used for the test set and the data provenance:

• Precision (Repeatability & Intermediate Precision):
  • Controls: Precinorm Protein and Precipath Protein.
  • Human Serum Samples: 4 human serum samples were used to evaluate repeatability and intermediate precision, plus 6 human serum samples for the specific results documented in the table. Each sample/control was analyzed with multiple aliquots (e.g., 2 aliquots for 21 days for precision).
  • Data Provenance: Not explicitly stated (e.g., country of origin), but it's noted as "human serum samples." The studies are prospective for the device evaluation.
• Analytical Sensitivity (LoB, LoD, LoQ):
  • LoB: Ten aliquots of analyte-free saline (N=60 determinations per lot).
  • LoD: Five samples of low analyte level human serum (N=60 determinations per lot).
  • LoQ: Nine low concentration human serum samples (N=25 determinations per sample per lot).
  • Data Provenance: Not explicitly stated for specific origin, but uses "analyte free saline" and "human serum."
• Linearity/Assay Reportable Range:
  • Samples: Dilution series prepared from native unmodified human serum sample pools, resulting in 15 levels. Each level measured in triplicate (n ≥ 3).
  • Data Provenance: "native unmodified human serum sample pools."
• Endogenous Interference:
  • Samples: Effects determined at 2 CRP levels (5-10 mg/L and 35-100 mg/L) utilizing 11-level serial dilution sets of interfering substances. Each level measured in triplicate.
  • Data Provenance: Not explicitly stated, likely lab-prepared samples with added interferents.
• Exogenous Interference (Drugs):
  • Samples: Effects determined at 2 CRP levels (5-10 mg/L and 35-100 mg/L) using pooled samples spiked with drugs. N=5 results per drug.
  • Data Provenance: Lab-prepared samples with added drugs.
• Sample Matrix Comparison:
  • Samples: Native samples from single donors drawn into serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma primary tubes.
  • Range Tested: 3.34 to 344 mg/L.
  • Data Provenance: "native samples (single donors)."
• Method Comparison to Predicate:
  • Samples: One hundred ten (N=110) native, unaltered serum samples.
  • Data Provenance: "native, unaltered serum samples."

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

This device is an in-vitro diagnostic (IVD) assay for quantitative determination of C-Reactive Protein (CRP). The "ground truth" for such devices is established by reference methods, certified reference materials, and accepted analytical techniques, not by expert interpretation in the same way imaging studies might use radiologists. The measurements for the test set samples (e.g., CRP concentrations) are determined by the analytical methods themselves, often verified against established standards or predicate devices. There is no mention of human experts establishing ground truth for the test set in the context of interpretation.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

For IVD assays, ground truth is typically analytical, not based on expert adjudication of observations. The "truth" is the measured concentration, often confirmed by multiple replicates or comparative methods, as opposed to a consensus reading process found in clinical imaging studies. Therefore, no adjudication method (like 2+1 or 3+1) is applicable or described here.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, an MRMC comparative effectiveness study was not performed. This device is an in-vitro diagnostic instrument for measuring a biomarker (CRP). It does not involve human readers interpreting images or results that would be "assisted" by AI. The device directly produces quantitative results.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done

Yes, the performance studies described are for the device (Tina-quant® C-Reactive Protein IV on a cobas c 501 analyzer) operating in a standalone capacity. It measures CRP in samples without human intervention in the interpretive output. The studies evaluate the analytical performance of the instrument and reagents themselves.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for this IVD device is based on:

• Analytical Standards: For LoB, LoD, LoQ, and Linearity, ground truth is established through statistical derivation from measurements of samples with known low or varying concentrations, or through the use of analyte-free samples or reference materials.
• Predicate Device Comparison: The "Method Comparison to Predicate" establishes the ground truth by comparing the device's results against a legally marketed and established predicate device (Roche Diagnostics C-Reactive Protein Gen.3), assuming the predicate provides the accepted reference values.
• Spiked Samples/Known Concentrations: For interference studies (endogenous and exogenous), ground truth is established by adding known amounts of interfering substances or drugs to samples with known CRP concentrations and observing the recovery of the expected CRP value.
• Certified Reference Materials (CRM): The "Traceability/Standardization" indicates that the candidate device is standardized against the certified reference material of IRMM (Institute for Reference Materials and Measurements) ERM-DA474/IFCC. This is a primary source of analytical ground truth.

8. The sample size for the training set

This document describes a premarket notification (510(k)) submission for a medical device. The "training set" concept is typically associated with machine learning or AI models. This device is an immunoturbidimetric assay, which is a traditional analytical chemistry method, not an AI/ML system. Therefore, there is no "training set" in the context of machine learning. The studies described are performance evaluations to demonstrate that the device meets its analytical specifications.

9. How the ground truth for the training set was established

As there is no "training set" for an AI/ML model for this traditional IVD assay, this question is not applicable. The device's performance is validated against analytical performance criteria as described above in point 7.

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The CRP Vario assay [CRPVa] is for in vitro diagnostic use in the quantitative immunoturbidimetric determination of C-reactive protein in human serum and plasma (sodium and lithium heparin) using the ARCHITECT c Systems. Measurement of C-reactive protein is useful in the detection and evaluation of infection, tissue injury and inflammatory disorders.

CRP Calibrators (including CRP Calibrator Set, CRP Calibrator HS and CRP Calibrator WR) are intended to be used for the calibration of the CRP Vario for the quantitative determination of C-reactive protein in human serum or plasma samples.

The CRP Vario assay is intended for the quantitative immunoturbidimetric determination of C-reactive protein in human serum and plasma. It is supplied as a two-reagent kit. The kit contains Reagent 1 (Glycine buffer) and Reagent 2 (Anti-CRP polyclonal antibodies adsorbed on latex particles). Two different sizes of the product are available. The submission also describes CRP Calibrators (CRP Calibrator Set, CRP Calibrator HS, and CRP Calibrator WR) which are prepared by diluting CRP with human serum and stabilized by adding sodium azide.

Here's an analysis of the acceptance criteria and study as described in the provided document:

Acceptance Criteria and Device Performance for CRP Vario

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document explicitly refers to an "Acceptance Criteria" column for Method Comparison in Table 15-3. For other performance characteristics, the "acceptance criteria" can be inferred by comparing the candidate device's stated performance to that of the predicate device, or by general statements about meeting recommendations or consistency with original submissions.

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

• Method Comparison Test Set:

  • High Sensitivity Method: N = 111 human serum samples
  • Standard Method: N = 119 human serum samples
  • Wide Range Method: N = 119 human serum samples
  • Data Provenance: The document states "Human serum samples, spanning the measuring range, were tested." No information is provided regarding the country of origin or whether the data was retrospective or prospective.

• Limit of Quantitation (LoQ) Test Set:

  • The study used serum pools diluted with SeraSub (a synthetic serum) to create 8 low-level analyte samples (0.08, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, and 0.005 mg/dL).
  • Each sample was tested in a minimum of 10 replicates per run, with 2 runs per day over 3 days, resulting in a total of 60 replicates per sample.

• Linearity Test Set:

  • A high CRP serum pool was mixed with a low serum pool to generate 12 concentrations.
  • Each concentration level was tested in triplicate determinations.

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

This section is not applicable to this type of device and study. The CRP Vario is an in vitro diagnostic device that quantifies C-reactive protein. Its performance is evaluated against reference methods (e.g., predicate devices, established analytical protocols) and CLSI guidelines, not against expert human interpretations of images or clinical reports. There are no "experts" establishing a subjective ground truth in the way described for AI in image analysis.

4. Adjudication Method for the Test Set

This section is not applicable. As an in vitro diagnostic device, the performance is determined by quantitative measurements and statistical comparisons with reference methods, not by adjudication of interpretations by multiple human readers.

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 evaluates human reader performance often in the context of imaging diagnostics. The CRP Vario is an in vitro diagnostic for laboratory analysis, not a device requiring human interpretation in this manner.

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

Yes, the studies reported here (Method Comparison, Linearity, Limit of Quantitation) are standalone performance evaluations of the CRP Vario assay. The device itself is an automated immunoturbidimetric system (ARCHITECT c8000 system) for quantitative measurement, operating without human interpretation of the final result, beyond standard laboratory quality control and result reporting.

7. The Type of Ground Truth Used

The "ground truth" for the performance evaluation of the CRP Vario was established by:

• Reference Methods / Predicate Device: For the Method Comparison study, the candidate CRP Vario (traceable to ERM-DA472/IFCC) was compared against a Beckman Coulter CRP Latex REF. OSR6199 (traceable to CRM 470) on an AU5800 platform.
• CLSI Guidelines: Formal CLSI (Clinical and Laboratory Standards Institute) protocols (EP09-A3 for Method Comparison, EP06-A for Linearity, EP17-A2 for LoQ) were followed, indicating that the acceptable statistical and analytical measures defined by these standards served as the basis for evaluating performance.
• Dilution Series / Known Concentrations: For Linearity and LoQ, the "ground truth" was derived from precisely prepared serum pools and their serial dilutions to known or targeted concentrations.

8. The Sample Size for the Training Set

This section is not applicable. The CRP Vario is a re-submission for a modification of an existing in vitro diagnostic device, not an AI/ML device that requires a distinct "training set" in the computational sense. Its performance is characterized through analytical verification and validation studies.

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

This section is not applicable for the reasons stated in point 8.

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