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.

Device Description

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.

AI/ML Overview

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.

Performance Characteristic	Acceptance Criteria (Implicit/Typical for IVD)	Reported Device Performance (Procise CRP)
Precision (Within-Laboratory)	Typically low Coefficient of Variation (CV%) for various CRP concentrations. Expected to be within acceptable limits for clinical diagnostic use.	Sample 1 (5.9 mg/L): Total SD=0.4, %CV=7.4 Sample 2 (9.2 mg/L): Total SD=0.8, %CV=8.6 Sample 3 (35.5 mg/L): Total SD=1.6, %CV=4.4 Sample 4 (75.1 mg/L): Total SD=4.6, %CV=6.1 Sample 5 (93.5 mg/L): Total SD=6.4, %CV=6.8 Sample 6 (125.6 mg/L): Total SD=10.0, %CV=8.0
Precision (Between-site)	Typically low Coefficient of Variation (CV%) across different sites. Expected to be within acceptable limits for clinical diagnostic use.	Sample 1 (7.27 mg/L): Total SD=0.6, %CV=7.6 Sample 2 (25.3 mg/L): Total SD=2.0, %CV=7.8 Sample 3 (72.7 mg/L): Total SD=6.5, %CV=9.0 QC1 (5.53 mg/L): Total SD=0.6, %CV=10.0 QC2 (48.7 mg/L): Total SD=4.5, %CV=9.3
Linearity	Linear regression R² value close to 1, slope close to 1, and intercept close to 0 within the measuring range.	Range (3.6 - 161.0 mg/L): Slope = 0.99 (95% CI: 0.97 – 1.00), Intercept = 0.05 (95% CI: -0.94 – 1.05), R² = 1.00
Analytical Specificity/Interference	Mean bias < 10% for individual recovery in the presence of various endogenous and exogenous interferents.	Endogenous Interferents: Hemolysate (300 mg/dL), Triglycerides (37 mmol/L), Bilirubin Conjugated (43 mg/dL), Bilirubin Unconjugated (40 mg/dL), Human anti-mouse Antibodies (HAMA) (200 IU/mL), Rheumatoid Factor (400 IU/mL). Exogenous Interferents: Acetaminophen (20 mg/dL), Ascorbic Acid (170 µmol/L), Acetylsalicylic Acid (65 mg/dL), Adalimumab (20 µg/mL), Amoxicillin (400 µmol/L), Ampicillin (500 µmol/L), Caffeine (600 µmol/L), Chloramphenicol (300 µmol/L), Erythromycin (400 µmol/L), Etanercept (0.1 µmol/L), Fluconazole (480 µmol/L), Gentamycin (120 µmol/L), Ibuprofen (2000 µmol/L), Infliximab (20 µg/mL), Methotrexate (1950 µmol/L), Penicillin (150 mg/L), Prednisone (1 µmol/L). Reported Performance: No significant interference was observed at the stated concentrations. Acceptance criterion of < 10% mean bias met.
Assay Reportable Range	Defined analytical measuring range.	5 to 150 mg/L
Traceability	Traceability to an internationally recognized standard.	Calibrators are traceable against ERM® -DA474/IFCC.
Real-time Reagent Stability	Demonstrated stability over a specified period at specified temperatures.	Stable for 24 months at ambient room temperatures (15-30°C).
Long-term Reagent Stability	Demonstrated stability over a specified period at specified temperatures.	Stable for up to 24 months at -80°C.
Shipping Stability	Demonstrated stability under simulated shipping conditions.	Reagent is stable for up to 72 hours at 38°C followed by six hours at 60°C under simulated shipping conditions.
Calibration Stability	Demonstrated stability of calibration cartridge over a specified period.	Calibration cartridge is stable at 23°C for up to 18.5 months.
Sample Stability	Demonstrated stability of CRP in serum samples under various storage conditions.	CRP in serum is stable for 11 days at 20-25°C, 2 months at 4-8°C, and 3 years at -20°C (Reference: WHO Publication WHO/DIL/LAB/99.1 Rev. 2. 2002, p28).
Detection Limit (LoB)	Defined limit of blank.	Claimed LoB is 1.1 mg/L (calculated at 0.9 mg/L).
Detection Limit (LoD)	Defined limit of detection.	Calculated LoD is 1.5 mg/L.
Limit of Quantitation (LoQ)	Defined limit of quantitation.	Claimed LoQ is 5.0 mg/L (calculated at 2.0 mg/L).
Accuracy (Instrument)	Recovery bias within ± 10% from expected values.	Recovery bias for all samples (1.0 to 41.2 mg/L CRP) was within ± 10% from the expected values based on dilutions of ERM® -DA474/IFCC.
Method Comparison with Predicate Device	Regression analysis (e.g., Passing-Bablok) showing good agreement with a predicate device.	N=81 serum samples (5.3 - 134.0 mg/L): Slope = 0.99 (95%CI: 0.95 - 1.01), Intercept = 0.20 (95% CI: -0.56 - 1.16). Bias at 5.0 mg/L medical decision point was 2.7%.
Expected Values/Reference Range	Establishment of a reference range in a healthy population.	Reference interval: 88.2% (150/170) of normal healthy subjects had concentrations within the consensus reference interval at 5 mg/L. The 95th percentile was 8.2 mg/L.

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.

Summary

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November 4, 2022

Procise Diagnostics Kurtis Bray Senior Director of Clinical Development and Regulatory Affairs 9449 Carroll Park Drive San Diego, California 92121

Re: K201256

Trade/Device Name: Procise CRP Assay Kit, ProciseDx Instrument, ProciseDx Calibration Cartridge Regulation Number: 21 CFR 866.5270 Regulation Name: C-reactive protein immunological test system Regulatory Class: Class II Product Code: DCK Dated: August 4, 2022 Received: August 5, 2022

Dear Kurtis Bray:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

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Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Ying Mao -S

Ying Mao, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Ouality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K201256

Device Name Procise CRP

Indications for Use (Describe)

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

Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)

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Image /page/3/Picture/0 description: The image shows the logo for ProciseDx. The logo consists of the word "ProciseDx" in a blue sans-serif font. To the right of the word is a stylized checkmark symbol that is split into two colors, blue and pink. The blue portion of the checkmark is on the bottom left, and the pink portion is on the top right.

510(k) Summarv

1. Submitter

ProciseDx, Inc. 9449 Carroll Park Drive San Diego, CA 92121 Telephone: (619) 354-2264 Contact Person: Kurtis Bray Date: October 24, 2022

2. Proprietary Names

ProciseDx Analyzer Procise C-Reactive Protein Procise CRP ProciseDx Calibration Cartridge

3. Predicate

Orion Diagnostica QuikRead go CRP K142993

4. Device Description

5. Intended Use

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Measurement of CRP aids in evaluation of injury to body tissues, infection, and 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.

Device & PredicateDevice(s):	K201256	K142993
Device Trade Name	Procise CRP	QuikRead Go CRP
General DeviceCharacteristic Similarities
Intended Use/IndicationsFor Use	The Procise CRP assayis a time-resolvedfluorescence energytransfer immunoassayfor the quantitativedetermination of C-Reactive Protein (CRP)levels in human serum.The test is carried outby means of theProciseDx Analyzer.Measurement of CRPaids in evaluation ofinjury to body tissues,infection, andinflammatory disorders.The instrument andassay are for use bytrained professionals inthe clinical laboratory.For in vitro diagnosticuse only. Not for pointof care use.	The QuikRead go®CRP test is animmunoturbidimetricassay for the in vitroquantitativedetermination of C-reactive protein (CRP)in K2-EDTA andlithium heparin wholeblood, K2-EDTA andlithium heparin plasma,and in serum samples.The test is carried outby means of theQuikRead goinstrument.Measurement of C-reactive protein aids inthe evaluation of injuryto body tissues, andinfection andinflammatory disorders.The instrument andassay are for use bytrained professionals inthe clinical laboratory.For in vitro diagnosticuse only. Not for point-of-care use.
Product Code	DCK	Same
Assay Type	Quantitative	Same
Sample Volume	20 µL	Same
Limit of Quantitation	5 mg/L	Same
Calibrators	The reagents are pre-calibrated.	Same
Traceability	ERM® -DA474/IFCC	Same
Assay principle	Immunoassay	Same
Assay Controls	Two (2) Levels, readyto use	Same
General DeviceCharacteristic Differences
Sample Type	Serum	SerumVenous whole blood(K2-EDTA)Venous whole blood(Li-Heparin)Plasma
Technology	Fluorescence resonanceenergy transfer (FRET)	Immunoturbidimetry
Instrument	ProciseDx Analyzer	QuikRead go Analyzer
Antibody	Fab' anti-human CRPantibody	Anti-human CRPF(ab)2 fragment
Reagent Storage	Ambient (15-30°C)	Refrigerated (2-8°C)
Assay Range	5.0-150 mg/L (serum)	5-200 mg/L (plasmaand serum)5-150 mg/L (wholeblood)

6. Comparison

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7. Standard/Special Control/Guidance Documents Referenced

ANSI Standard "HL7 Messaging Standard Version 2.7.1, An Application Protocol for . Electronic Data Exchange in Healthcare Environments - 2012
CLSI EP05-A3: Evaluation of Precision of Quantitative Measurement Procedures- Third ● Edition - October 2014
CLSI EP06-A: Evaluation of the Linearity of Quantitative measurement Procedures A ● Statistical Approach - First Edition - April 2003
CLSI EP07-3rd Edition Interference Testing in Clinical Chemistry April 2018 ●
CLSI EP09c Measurement Procedure Comparison and Bias Estimation Using Patient . Samples. Third edition - June, 2018
. CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures - Second Edition - June 2012
CLSI EP25-A: Evaluation of Stability of In Vitro Diagnostic reagents- First Edition-. September 2009
. CLSI C28-A3: Defining, Establishing, and Verifying Reference Intervals in the Clinical laboratory- Third Edition - November 2008

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Electrical Safety IEC 61010-1:2010 (third edition), Safety requirements for electrical . equipment for measurement, control, and laboratory use - Part 1: General requirements
EN ISO 13485: Medical devices Ouality management systems Requirements for . regulatory purposes
EN ISO 14971: Medical devices Application of risk management to medical devices ●
EN ISO 15223-1: Medical devices Symbols to be used with medical device labels, ● labelling and information to be supplied - Part 1: General requirements (ISO 15223-1:2016, Corrected version 2016-12-15)
EN ISO 18113-1: In vitro diagnostic medical devices Information supplied by the . manufacturer (labelling). Part 1: Terms, definitions and general requirements
EN ISO 18113-3: In vitro diagnostic medical devices Information supplied by the ● manufacturer (labelling) - Part 3: In vitro diagnostic instruments for professional use
EN 61326-1; 2013/IEC 61326-1:2012, Electrical equipment for measurement, control ● and laboratory use - EMC requirements - Part 1: General requirements
EN 62366-1: Application of usability engineering to medical devices ●
General Principles of Software Validation Guidance for Industry and FDA Staff. January ● - 2002
. Guidance for Industry - Review Criteria for Assessment of C - Reactive Protein (CRP), High Sensitivity C-Reactive Protein (hsCRP) and Cardiac C-Reactive Protein (cCRP) Assays.
Guidance for the Content of Premarket Submissions for Software Contained in Medical ● Devices Guidance for Industry and FDA Staff. May - 2005
Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover ● Human Specimens that are Not Individually Identifiable, April 2006
IEC 62304 Medical device software Software life cycle processes ●
ISTA Procedure 2A: Partial simulation testing of individual packaged-products weighing ● 150 lb (68kg) or less when prepared for shipment
Off-The-Shelf Software Use in Medical Devices. Guidance for Industry and Food and Drug Administration Staff - September 2019

8. Performance Characteristics

A Analytical Performance:

1. Precision/Reproducibility:
- Within-Laboratory Imprecision: a.

The study was conducted based on CLSI guideline EP05-A3, where six serum samples were tested in duplicates per run, two runs per day for 20 days using two reagent lots on two analyzers (each lot per each analyzer). Each sample was tested to generate a total of 160 test results (2 replicates x 2 runs x 20 days x 2 lots = 160). The total SD and CV% calculation was based on the within-run, between-run, between-day, and between-lot data. The results are shown in the table below.

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Sample	N	Mean (mg/L)	Within-run		Between-run		Between-day		Between-lot		Total
			SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
1	160	5.9	0.4	6.2	0.0	0.0	0.1	1.2	0.2	3.8	0.4	7.4
2	160	9.2	0.6	6.4	0.0	0.0	0.1	0.7	0.5	5.7	0.8	8.6
3	160	35.5	1.4	3.9	0.7	2.0	0.0	0.0	0.3	0.8	1.6	4.4
4	160	75.1	2.8	3.7	0.8	1.1	0.9	1.2	3.4	4.6	4.6	6.1
5	160	93.5	4.3	4.6	0.0	0.0	2.3	2.5	4.2	4.5	6.4	6.8
6	160	125.6	6.8	5.4	0.0	0.0	2.3	1.9	7.0	5.5	10.0	8.0

b. Between-site imprecision:

The study was conducted at three different sites using five serum samples (3 patients and 2 QCs) with different CRP concentrations across the measuring interval. Within-run, between-run, between-day, between-operator/instrument, between-site, and total SDs and %CVs were calculated based on 180 determinations per sample performed with three replicates per run, two runs per day for five different days on two operators/instruments at three test sites using a single reagent lot (3 replicates x 2 runs x 5 days x 2 instruments x 3 sites = 180). The results are shown in the table below.

Sample	N*	Mean(mg/L)	Within-run		Between-run		Between-day		Between-instrument		Between-site		Total
			SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
1	179	7.27	0.5	6.6	0.0	0.0	0.0	0.0	0.1	1.6	0.2	2.1	0.6	7.6
2	179	25.3	1.7	6.8	0.0	0.0	0.3	1.3	0.0	0.0	0.7	2.7	2.0	7.8
3	177	72.7	6.2	8.5	0.0	0.0	0.7	0.9	0.0	0.0	0.0	0.0	6.5	9.0
QC1	179	5.53	0.5	8.9	0.0	0.0	0.0	0.0	0.1	0.8	0.3	4.6	0.6	10.0
QC2	178	48.7	4.2	8.6	0.0	0.0	0.0	0.0	0.0	0.0	1.8	3.7	4.5	9.3

98.3% (177/180) to 99.4% (179/180) of the test results were included in analysis.

2. Linearity:

The linearity was evaluated using a series of pooled human serum samples at 11 dilution levels prepared to evenly cover the CRP concentration range of 3.6 to 161.0 mg/L. Each sample dilution was measured in one run with three or four replicates; the mean of the three replicates or four replicates was calculated for each sample. Linear regression analysis of . expected value vs observed CRP value was performed to determine whether the sample set exhibits linearity. The linear regression results for nine samples within the measuring interval are shown in the table below.

Range (mg/L)	Slope(95%CI)	Intercept(95% CI)	R2
3.6 - 161.0	0.99	0.05	1.00

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Range (mg/L)	Slope(95%CI)	Intercept(95% CI)	R2
	(0.97 – 1.00)	(-0.94 – 1.05)

3. Analytical Specificity/Interference:

To investigate the test performance with presence of potential endogenous and exogenous interferents, three pooled human serum samples with various CRP concentrations (12.3, 52.9, and 89.7 mg/L) were prepared and spiked with potential interfering substances. The CRP level in the test samples was measured in three replicates and the recovery in relation to the unspiked sample without interferent was calculated. The acceptance criterion was < 10% in the mean bias for the individual recovery. No significant interference was observed at the concentration of the potential interfering substances as shown in the table below.

Endogenous Interferent	Concentration
Hemolysate	300 mg/dL
Triglycerides	37 mmol/L
Bilirubin Conjugated	43 mg/dL
Bilirubin Unconjugated	40 mg/dL
Human anti-mouse Antibodies (HAMA)	200 IU/mL
Rheumatoid Factor	400 IU/mL

Exogenous Interferent	Concentration
Acetaminophen	20 mg/dL
Ascorbic Acid	170 µmol/L
Acetylsalicylic Acid	65 mg/dL
Adalimumab	20 µg/mL
Amoxicillin	400 µmol/L
Ampicillin	500 µmol/L
Caffeine	600 µmol/L
Chloramphenicol	300 µmol/L
Erythromycin	400 µmol/L
Etanercept	0.1 µmol/L
Fluconazole	480 µmol/L
Gentamycin	120 µmol/L
Ibuprofen	2000 µmol/L
Infliximab	20 µg/mL
Methotrexate	1950 µmol/L
Penicillin	150 mg/L
Prednisone	1 µmol/L

4. Assay Reportable Range:

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The analytical measuring range of Procise CRP is 5 to 150 mg/L.

1. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
- a. Traceability: The calibrators are traceable against ERM® -DA474/IFCC.
- b. Real-time Stability: The reagent stability at ambient room temperatures was evaluated by testing three serum samples (~ 5, ~ 50, and ~100 mg/L) in six replicates each, using two lots of Procise CRP at 15°C, 23°C, and 30°C. The Procise CRP is stable for 24 months at ambient room temperatures at 15-30°C.
- c. Long-term stability: The reagent stability for long-term storage was evaluated by testing ten native and three pooled human serum samples with CRP concentrations ranged 5.0 to 73.3 mg/L, using two reagent lots. The Procise CPR is stable for up to 24 months at -80°C.
- d. Shipping Stability: The shipping stability was evaluated by testing two serum samples with CRP concentrations at ~5 and ~50 mg/L , using four pouched CRP Assay kits, each containing 20 Procise CRP cartridges (regent), 20 buffer bulbs and 20 minivettes. The packed CRP Assay Kits were placed at 38°C for 72 hours and then at 60°C for six hours followed by a stress test in a sequence of compression, random vibration, drop (in carton), random vibration, low pressure, and a bubble test. The Procise CPR reagent is stable for up to 72 hours at 38°C followed by six hours at 60°C under the simulated shipping conditions.
- e. Calibration Stability: Stability of the calibration cartridge was evaluated on ProciseDx instrument by testing six calibration cartridges stored at 23°C after an initial calibration. The CRP calibration cartridge is stable at 23°C for up to 18.5 months.
- Sample Stability: CRP in serum is stable for 11 days at 20-25°C, 2 months at 4-8°C, and f. 3 years at -20℃. (Reference: Use of Anticoagulants in Diagnostic Laboratory Investigations. WHO Publication WHO/DIL/LAB/99.1 Rev. 2. 2002, p28.)
1. Detection Limit:

For limit of blank (LoB), a set of four analyte depleted serum samples was investigated using two reagent lots over three days. Each sample was tested in five replicates per run, one run per day for three days to reach a total of 60 measurements per reagent lot. LoB was determined per CLSI EP17-A2. The higher value from both lots was taken for the LoB at 0.9 mg/L. The claimed LoB is 1.1 mg/L.

For limit of detection (LoD), a set of five low level serum samples in the range below the measuring interval was investigated using two reagent lots. Each sample was tested in four replicates per run, one run per day for three days to reach a total of 60 measurements per

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reagent lot. The LoD was determined per CLSI EP17-A2. The higher value from both lots was taken for the LoD at 1.5 mg/L.

For limit of quantitation (LoQ), a set of five low measurand content serum samples from the lower end of the measuring interval was investigated. Each sample was tested in four replicates per run, one run per day for three days using two lots to reach a total of 24 measurements. The LoO was determined as 2.0 mg/L following CLSI EP17-A2, the sample with the highest value for the %CV in accordance with the specification for both reagent lots (<20%). The claimed LoQ is 5.0 mg/L.

1. Accuracy (Instrument):
  The ProciseDx Analyzer accuracy was evaluated using ERM® -DA474/IFCC that was serially diluted with CRP-depleted human serum for preparation of 11 dilution levels, ranging 1.0 to 41.2 mg/L CRP. Each diluted serum sample was tested in three replicates while the original ERM® -DA474/IFCC (highest concentration) was tested in six replicates. The recovery bias for all samples was with ± 10% from the expected values based on dilutions of ERM® -DA474/IFCC.

B Comparison Studies:

1. Method Comparison with Predicate Device:
  A total of 81 serum samples spanning the assay measuring interval were tested by both the Procise CRP and a comparator (Orion QuikRead go® CRP). Measurement comparison between these two assays was evaluated using Passing-Bablok regression analysis and the result is shown in the table below. At the medical decision point of 5.0 mg/L, the calculated bias was 2.7%.

Sample (N)	Range (mg/L)	Slope(95%CI)	Intercept(95% CI)
81	5.3 - 134.0	0.99(0.95 - 1.01)	0.20(-0.56 - 1.16)

C Clinical Studies:

1. Clinical sensitivity: Not applicable
1. Clinical specificity: Not applicable
1. Other clinical supportive data (when a. and b. are not applicable): Not applicable
1. Clinical cut-off: Not applicable

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D Expected Values/Reference Range:

The reference range study was conducted by testing normal healthy subjects. The subjects with chronic diseases, including obesity (BMI > 30, https://www.cdc.gov/obesity/aboutobesity/index.html) were excluded in the analysis. A total of 170 samples (88 males at 18-72 years and 82 females at 21-69 years) were included in the analysis. Of 170 tested samples, 150 samples (150/170, 88.2%) had concentrations within the consensus reference interval at 5 mg/L taken from the literature reference*. The 95th percentile was 8.2 mg/L. Each laboratory should establish its own reference range.

*The expected value in the normal population aged 20 to 60 years is < 5mg/L per literature (Roberts WL, McMillin GA, Burtis CA, Bruns DE. Reference Information for the Clinical Laboratory, Tietz Textbook of Clinical Chemistry and Molecular Diagnostics; 4th Ed., Burtis CA, Ashwood ER, Bruns DE (2006): 2263).

9. Conclusion

The submitted information in this premarket notification is complete and supports a decision of substantial equivalence to the predicate device.

Regulation Number and Section

§ 866.5270 C-reactive protein immunological test system.

(a)
Identification. A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.(b)
Classification. Class II (performance standards).