The C-Reactive Protein Kit for use on SPAPLUS is intended for the quantitative in vitro determination of C-reactive protein (CRP) concentration in serum. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues and for evaluation of infection, tissue injury, and inflammatory disorders. This product is suitable for use on the SPAPLUS analyser.

Device Description

The C-Reactive Protein Kit for use on SPAPLUS is comprised of the following reagents:

Antiserum: Supplied in stabilised liquid form. Preservatives: 0.099% sodium azide, TRIS pH 8.0.

Calibrator and Controls: Pooled human serum, supplied in stabilised liquid form. Containing 0.099% sodium azide, as preservative. The concentration given on the quality control certificate has been obtained by comparison with the international reference standard ERM-DA474.

Reaction Buffer: Containing 0.099% sodium azide, TRIS pH 7.5 as preservatives.

AI/ML Overview

The provided document is a 510(k) premarket notification for a C-Reactive Protein Kit for use on the SPAPLUS analyzer. It details the device's intended use, comparison to a predicate device, and performance characteristics.

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

1. Table of Acceptance Criteria and Reported Device Performance

Performance Characteristic	Acceptance Criteria	Reported Device Performance
Precision/Reproducibility
Total precision	%CV < 10%	All samples met: Sample 1 (8.4%), Sample 2 (7.1%), Sample 3 (2.5%), Sample 4 (1.8%)
Within-run precision	%CV < 5%	All samples met: Sample 1 (1.9%), Sample 2 (1.3%), Sample 3 (0.6%), Sample 4 (0.5%)
Between-run precision	%CV < 8%	All samples met: Sample 1 (4.5%), Sample 2 (3.8%), Sample 3 (1.9%), Sample 4 (1.8%)
Between-day precision	%CV < 8%	All samples met: Sample 1 (6.9%), Sample 2 (5.8%), Sample 3 (1.5%), Sample 4 (0.0%)
Linearity/Assay Reportable Range
%CV for each sample	≤8%	All samples met (highest %CV was 1.9%)
Allowable nonlinearity	± 10% (Implicitly met as no issues were reported and linearity was "assessed across the curve width at the standard sample dilution (1/1)")	Results met Acceptance criteria for CV<8%. (Nonlinearity explicitly stated as met)
Analytical Specificity (Interference Testing)
Non-interference claim	Mean results from spiked samples must be within 10% of the mean of control samples	Assay not affected by: Haemoglobin (5g/L), Bilirubin (200mg/L), Rheumatoid Factor (2417IU/mL), Intralipid (250mg/dL), and 14 therapeutic drugs.
Method Comparison with Predicate Device	Clinically concordant results (No specific numeric acceptance criteria for regression statistics provided, but clinical concordance is key)	99.6% of samples tested gave clinically concordant results.

2. Sample Sizes and Data Provenance

Precision/Reproducibility: 4 serum samples were tested. The study design followed CLSI EP5-A2, with 2 runs per day (each in duplicate) over 21 days.
Linearity/Assay Reportable Range: A series of 13 samples was tested in 3 replicates.
Detection Limit: LoB was based on 60 determinations of a blank sample. LoQ study was carried out on two reagent lots.
Analytical Specificity: Serum samples with targeted CRP concentrations (elevated ~60 mg/L and near reference interval ~5 mg/L) were spiked with interfering substances and tested in replicates of 3.
Method Comparison with Predicate Device: A total of 225 serum samples were assayed.
Data Provenance: The document does not explicitly state the country of origin for the samples. It mentions "normal donors" and "clinical samples" for the method comparison study, implying that the data is from relevant patient populations, but does not specify if it was retrospective or prospective. Given the nature of an in vitro diagnostic device for laboratory testing, the samples are collected from individuals and then analyzed in a lab setting.

3. Number of Experts and Qualifications for Ground Truth for Test Set

The document does not describe the use of human experts to establish ground truth for the test set in the conventional sense of, for example, image interpretation by radiologists. This device is an in vitro diagnostic (IVD) test, where the "ground truth" for method comparison and performance evaluation is typically established by:

Reference Methods/Predicate Devices: The predicate device itself (Roche Diagnostics Tina-Quant C-Reactive Protein Gen. 3) serves as a comparative "gold standard" or established method for evaluating if the new device produces similar results.
International Reference Standards: The calibration of the CRP assay is traceable to the international reference standard ERM-DA474, which ensures accuracy against a widely recognized reference material.

Therefore, the concept of "number of experts" and their qualifications as typically applied to, for instance, image analysis, is not directly applicable here.

4. Adjudication Method for the Test Set

Not applicable. As described above, the "ground truth" is based on reference methods, predicate device comparison, and international standards, not subjective expert assessment requiring adjudication.

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

No. This is an in vitro diagnostic device, not a device requiring human reader interpretation (e.g., medical imaging AI). Therefore, an MRMC study is not relevant or applicable. The AI/human-in-the-loop concept does not apply to this type of device.

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

Yes, the studies presented (Precision, Linearity, Detection Limit, Analytical Specificity) are all standalone performance evaluations of the device (C-Reactive Protein Kit for use on SPAPLUS) itself. The in vitro diagnostic device is an automated system run on an analyzer (SPAPLUS), and its performance is evaluated in isolation from human interpretation beyond routine laboratory operation and quality control. The method comparison study also evaluates the device's analytical performance against a predicate.

7. Type of Ground Truth Used

Reference Methods/Predicate Device: For the method comparison study, the results from the legally marketed predicate device (Roche Diagnostics Tina-Quant C-Reactive Protein Gen. 3) served as the comparative data point.
International Reference Standards: The calibration of the new device is traceable to the international reference standard ERM-DA474, which provides the ultimate analytical ground truth for CRP concentration.
Spiked Samples/Known Concentrations: For studies like linearity, detection limit, and analytical specificity (interference), samples with known or spiked concentrations of CRP and interfering substances are used to evaluate the device's accuracy and resistance to interference.

8. Sample Size for the Training Set

Not applicable. This document describes an in vitro diagnostic device that is based on immunoturbidimetry, a chemical reaction and measurement process. It's not an AI/Machine Learning device that requires a "training set" in the computational sense. The "training" here refers to the calibration of the instrument using calibrator material traceable to reference standards.

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

Not applicable, as there is no "training set" in the AI/ML sense. For the calibration (which could be conceptually similar to "training" in an analytical device context):

Calibrators traceable to ERM-DA474: The calibrators included in the kit are pooled human serum with concentrations established by comparison with the international reference standard ERM-DA474. This established value serves as the ground truth for the calibration process, ensuring accuracy across measurements.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

April 5, 2017

The Binding Site Group Ltd Ms. Kirsty Samuels Regulatory Affairs Officer 8 Calthorpe Road, Edgbaston Birmingham, West Midlands, B15 1QT UK

Re: K161982

Trade/Device Name: C-Reactive Protein Kit for Use on SPAPlus Regulation Number: 21 CFR 866.5270 Regulation Name: C-Reactive Protein Immunological Test System Regulatory Class: II Product Code: DCN Dated: March 9, 2017 Received: March 10, 2017

Dear Ms. Samuels:

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. 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.

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 Parts 801 and 809); medical device reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the

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electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours.

Kelly Oliner -S

FOR

Leonthena R. Carrington, MS, MBA, MT(ASCP) Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K161982

Device Name

C-Reactive Protein Kit for use on SPAPLUS

Indications for Use (Describe)

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

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C-Reactive Protein kit for use on SPAPLUS 510(k) Summary

A. 510(k) Number:

K161982

B. Purpose for Submission:

New device

C. Measurand:

C-Reactive Protein

D. Type of Test:

Quantitative immunoturbidimetry

E. Applicant:

The Binding Site

F. Proprietary and Established Names:

C-Reactive Protein Kit for use on SPAPLUS®

G. Regulatory Information:

1. Regulation section:
  21 CFR 866.5270, C-reactive protein immunological test system.
1. Classification:
  Class II
1. Product code:
  DCN, System, Test, C-Reactive Protein
1. Panel:
  Immunology (82)

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H. Intended use:

1. Intended use(s):

The C-Reactive Protein Kit for use on SPAPLUS is intended for the quantitative in vitro determination of C-reactive protein (CRP) concentration in serum.

2. Indication(s) for use:

Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues and for evaluation of infection, tissue injury, and inflammatory disorders. This product is suitable for use on the SPAPLUS analyser.

3. Special conditions for use statement(s):

Prescription use only

4. Special instrument requirements:

The Binding Site SPAPLUS analyser

l. Device Description:

The C-Reactive Protein Kit for use on SPAPLUS is comprised of the following reagents:

Antiserum: Supplied in stabilised liquid form. Preservatives: 0.099% sodium azide, TRIS pH 8.0.

Reaction Buffer: Containing 0.099% sodium azide, TRIS pH 7.5 as preservatives.

J. Substantial equivalence information:

1. Predicate device name(s) and 510(k) number(s):

Roche Diagnostics Tina-Quant C-Reactive Protein Gen. 3 (K083444)

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2. Comparison with predicate:

Similarities

Item	Device	Predicate
Intended use	Quantitative in vitro determination ofC-reactive protein (CRP).	Same.
Method	Turbidimetry	Same.
Reference Interval	<5mg/L	Same.
Sample type	Serum	Serum (also Li-heparin and EDTAplasma)

Differences

Item	Device	Predicate
Measuring Range	5-250mg/L (neat)50-2500mg/L (1/10 dilution)	0.3-350mg/L (neat)0.6-700mg/L (1/2 dilution)
Analyser	SPAPLUS	Hitachi 912, 917, Modular P
Antibody	anti- human CRP (goat)	anti-human CRP (mouse)
Open vial stability	Three months at 2 to 8°C	Not stated.
On board stability	30 days.	84 days opened and refrigeratedon the analyser.
Reagent	Antiserum	Latex particles coated with anti-CRP(mouse)
Calibration	5 point, calibrator set	5 point, single calibrator diluted onanalyser
Wavelength	340nm	570nm/800nm
Traceability	ERM-DA474	CRM470

K. Standards and Guidance documents referenced:

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 Industry and FDA Staff

CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second edition

CLSI EP7-A2 Interference Testing in Clinical Chemistry, Approved Guideline - Second Edition

CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach

CLSI EP5-A2 Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline - Second Edition

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L. Test Principle:

The determination of soluble antigen (CRP) concentration by turbidimetric methods involves the reaction with specific antiserum (anti-CRP) to form insoluble complexes. When light is passed through the suspension formed a portion of the light is transmitted and focused onto a photodiode by an optical lens system. The amount of transmitted light is indirectly proportional to the specific protein concentration in the test sample. Concentrations are automatically calculated by reference to a calibration curve stored within the instrument.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

Precision/Reproducibility: a.

The studies were based on CLSI EP5-A2, where 4 sera samples (targeted to 6.025mg/L, 8.643mg/L, 21.342mg/L and 65.165mg/L) were tested in 2 runs per day (each of the 2 runs in duplicate) over 21 days using 1 reagent lot on 3 analysers. Results met the acceptance criteria for total precision (%CV<10%), within-run precision (%CV<5%), between-run precision (%CV<8%), and between-day precision (%CV<8%).

Sample		1	2	3	4
Mean concentration (mg/L)		6.025	8.643	21.342	65.165
Total precision	SD	0.5086	0.6111	0.5320	1.2034
	%CV	8.4	7.1	2.5	1.8
Within-run precision	SD	0.1129	0.1102	0.1314	0.3034
	%CV	1.9	1.3	0.6	0.5
Between-run	SD	0.2723	0.3262	0.4082	1.1645
precision	%CV	4.5	3.8	1.9	1.8
Between-day precision	SD	0.4144	0.5049	0.3147	0.0000
	%CV	6.9	5.8	1.5	0.0
Between-instrument precision	SD	0.335	0.529	0.037	0.434
	%CV	5.6	6.0	0.2	0.7

b. Linearity/assay reportable range:

The studies followed CLSI EP6-A, whereby linearity was assessed across the curve width at the standard sample dilution (1/1).

The acceptance criteria were that the %CV for each sample should be ≤8% and the allowable nonlinearity was ± 10%.

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% High pool	MeanResult	SD	%CV
100.0%	315.333	2.574	0.8
90.0%	288.100	5.110	1.8
80.0%	258.867	3.313	1.3
70.0%	224.033	1.457	0.7
60.0%	198.900	3.175	1.6
50.0%	176.533	0.902	0.5
40.0%	144.433	1.250	0.9
30.0%	108.233	1.079	1.0
20.0%	71.400	0.265	0.4
10.0%	35.167	0.681	1.9
1.5%	5.700	0.100	1.8
1.0%	4.133	0.058	1.4
0.5%	2.800	0.000	0.0

A series of 13 samples was tested in 3 replicates. Results met the Acceptance criteria for CV<8%.

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

i) Traceability:

The calibration of the assay is traceable to the international reference standard ERM-DA474.

ii) Kit Stability:

Real-time stability – A study to establish shelf-life stability (from the date of manufacture when stored at recommended temperature 2-8°C) of the SPAPLUS CRP Kit is on-going, Currently available data supports a 5-month stability claim.

Open-vial stability - The SPAPLUS CRP Kit reagents can be stored, opened at 2 - 8℃ for up to 3 months.

On-board stability - The SPAPLUS CRP Kit reagents can be stored on-board the Optilite Analyser for at least 30 days.

d. Detection limit.

The analytical sensitivity was determined in accordance with CLSI EP17-A2. The Limit of Blank (LoB) was based on 60 determinations of a blank sample and was estimated as the 95% percentile of the distribution. The LoQ study was carried out on two reagent lots. The highest LoQ from the results of the two reagent lots was used as the overall LoQ result. The highest LoD calculated from the two LoQ studies was used as the overall LoD.

The Limit of Detection (LoD) was calculated for both reagent lots according to the equation: the LoB + 1.645 x SD where SD was based on the standard deviation of the sample used for the LoQ claim.

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The LoQ was calculated and the total error % (12%) was within the maximum allowable total error.

LoB	LoD	LoQ
0.5mg/L	0.7529mg/	5.0mg/L

e. Analytical specificity:

Interferences were assessed according to CLSI EP7-A2 by testing serum samples with CRP concentrations falling above (elevated) (target 60mg/L) or close to the limits of the reference interval (target 5mg/L). Each sample was spiked with interfering substances and tested in replicates of 3. For non-interference to be claimed, the mean results from the spiked samples must be within 10% of the mean of the control samples.

Haemoglobin, Bilirubin and RF results: The data demonstrated that the assay was not affected by high levels of the following substances: haemoglobin (5g/L), bilirubin (200mg/L) and Rheumatoid Factor (RF) (2417IU/mL).

Intralipid results: The data demonstrated that the assay was not affected by intralipid at the level of 250mg/dL.

Drug Interference results: The data demonstrated that the assay was not affected by the 14 therapeutic drugs tested at the concentrations givenbelow.

Drug	Concentration tested
Acetaminophen	1324µmol/L
Acetylsalicylic Acid	1.95mmol/L
Amoxicillin	206µmol/L
Ascorbic Acid	342µmol/L
Caffeine	308µmol/L
Cefotaxime	673µmol/L
Theophylline	222µmol/L
Chloramphenicol	155µmol/L
Cimetidine	79.2µmol/L
Digoxin	7.8nmol/L
Fluconazole	245µmol/L
Ibuprofen	606.25µmol/L
Penicillin	75mg/L
Phenytoin	198µmol/L

f. Assay cut-off:

Not applicable

1. Comparison studies:
  a. Method comparison with predicate device:

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A total of 225 serum samples spanning the dynamic range were assayed in singlicate by both the CRP Kit on the SPAPLUS Analyser and the Tina-Quant C-Reactive Protein Gen. 3 assay for use on the Modular P analyser. The samples included 82 normal donors and 143 clinical samples.

Regressionfit	RegressionEquation	Slope(95% CI)	Intercept(95% CI)
WeightedLinear	Y = 1.064x + 1.14	1.05 to 1.08	0.89 to 1.40
Passing-Bablok	Y = 1.021x + 3.22	1.01 to 1.04	2.32 to 4.27
WeightedDeming	Y = 1.062x + 1.13	1.05 to 1.08	0.74 to 1.52

Regression statistics are based on the balance of the paired results.

99.6% of samples tested gave clinically concordant results on both analysers.

b. Matrix comparison:
None
1. Clinical studies:
- a. Clinical Sensitivity:

Not applicable

b. Clinical specificity:
Not applicable

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

Not applicable

1. Clinical cut-off:
  Not applicable
1. Expected values/Reference range:
  Consensus reference interval for adults: <5 mg/L

Reference: Dati F, Schumann G, Thomas L et al. Consensus of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins in serum based on the standardization against the IFCC/BCR/CAP reference material (CRM 470). Eur J. Clin Chem Clin Biochem 1996;34:517-520.

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N. Proposed Labeling:

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

O. Conclusion:

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

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).