System reagent for the quantitative determination of Ceruloplasmin (CER) in human serum and plasma on Beckman Coulter AU analyzers as an aid in the diagnosis of copper metabolism disorders.

Device Description

The Ceruloplasmin reagent kit is in a liquid, ready to use form. It is available in one format OSR6164 which consists of 4 x 18mL R1 vials and 4 x 5ml R2 vials. The calibrator is a Beckman Coulter Serum protein multi-calibrator ODR3023 which is sold separately. Ceruloplasmin is a turbidimetric method the basis for this method is the measurement of the decrease in light transmitted (increase in absorbance) through the particles suspended in solution as a result of complexes formed during the antigen-antibody reaction. The Ceruloplasmin reagent is designed for optimal performance on the Beckman Coulter AU analyzers.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Beckman Coulter Ireland Inc. Ceruloplasmin reagent, based on the provided document:

Acceptance Criteria and Device Performance

Acceptance Criteria	Reported Device Performance	Meet Criteria
Method Comparison
Slope: 0.900-1.100	1.056	Pass
Intercept: ≤ ± 30mg/L	-26.10mg/L	Pass
r: ≥0.975	0.990	Pass
N: ≥100	120	Pass
Within Run Precision
Pool 1 (95.99 mg/L): ≤5% CV or SD ≤1 mg/dL (10mg/L)	1.10% CV (1.042 SD)	Pass
Pool 2 (148.36 mg/L): ≤5% CV or SD ≤1 mg/dL (10mg/L)	1.10% CV (1.70 SD)	Pass
Pool 3 (254.17 mg/L): ≤5% CV or SD ≤1 mg/dL (10mg/L)	0.90% CV (2.30 SD)	Pass
Pool 4 (596.43 mg/L): ≤5% CV or SD ≤1 mg/dL (10mg/L)	0.90% CV (5.46 SD)	Pass
Pool 5 (915.61 mg/L): ≤5% CV or SD ≤1 mg/dL (10mg/L)	0.7% CV (6.78 SD)	Pass
Pool 6 (1791.94 mg/L): ≤5% CV or SD ≤1 mg/dL (10mg/L)	0.5% CV (9.52 SD)	Pass
Total Precision
Pool 1 (95.99 mg/L): ≤10% CV or SD ≤2 mg/dL (20mg/L)	6.7% CV (6.44 SD)	Pass
Pool 2 (148.36 mg/L): ≤10% CV or SD ≤2 mg/dL (20mg/L)	2.80% CV (4.09 SD)	Pass
Pool 3 (254.17 mg/L): ≤10% CV or SD ≤2 mg/dL (20mg/L)	2.20% CV (5.70 SD)	Pass
Pool 4 (596.43 mg/L): ≤10% CV or SD ≤2 mg/dL (20mg/L)	1.90% CV (11.36 SD)	Pass
Pool 5 (915.61 mg/L): ≤10% CV or SD ≤2 mg/dL (20mg/L)	1.6% CV (14.51 SD)	Pass
Pool 6 (1791.94 mg/L): ≤10% CV or SD ≤2 mg/dL (20mg/L)	1.4% CV (25.23 SD)	Pass

Study Details:

Sample size used for the test set and the data provenance:
- Method Comparison: 120 samples. The document does not specify the country of origin or whether the data was retrospective or prospective.
- Precision Study: The report lists 6 "pools" with varying concentrations. The number of individual samples within each pool or the total number of samples used for the precision study is not explicitly stated beyond what is implied by the "Pool" structure. The data provenance is also not specified.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This is a chemistry test system (in vitro diagnostic reagent) for quantitative determination of ceruloplasmin. The ground truth (reference values) for the method comparison study was established using a predicate device, the Siemens N Antisera to Human Ceruloplasmin. For precision, the ground truth is based on the inherent variability measurements of the device itself.
- Therefore, the concept of "experts establishing ground truth" in the way it might apply to image-based diagnostic AI is not directly applicable here. No human experts are explicitly mentioned as establishing the ground truth for these quantitative measurements.
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Not applicable. This device provides quantitative measurements, which are directly compared to values obtained from a predicate device or assessed for statistical precision, rather than requiring subjective expert adjudication of qualitative interpretations.
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. This is an in-vitro diagnostic reagent, not an AI-assisted diagnostic tool for human readers. Therefore, an MRMC study is not relevant.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, essentially. The stated performance data (Method Comparison, Precision) reflects the standalone performance of the Ceruloplasmin reagent system on Beckman Coulter AU analyzers without direct human intervention in the result generation process, beyond operating the analyzer and performing necessary calibration/quality control.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For the Method Comparison study, the ground truth was established by another legally marketed predicate device: Siemens N Antisera to Human Ceruloplasmin. This is a form of comparative ground truth against an established method.
- For the Precision study, the ground truth is statistical, derived from repeated measurements of samples to quantify variability relative to the mean of those measurements.
The sample size for the training set:
- This document describes a 510(k) premarket notification for an in-vitro diagnostic reagent. It does not refer to a "training set" in the context of machine learning or AI. The development process for such a reagent would involve internal verification and validation studies during manufacturing, but these are not typically referred to as "training sets" in the same way as for AI. The document only reports performance data, not development data.
How the ground truth for the training set was established:
- Not applicable, as there is no "training set" described in the context of AI. For the development and validation of an IVD reagent, ground truth would be established through a combination of using certified reference materials, comparison to existing gold standard methods, and defined analytical protocols to ensure accuracy and precision. However, these specific details are not provided in this 510(k) summary.

Summary

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

January 9, 2016

Beckman Coulter Ireland Inc. Ms. Marguerita Sweeney Regulatory Affairs Manager Lismeehan, O'Callaghan's, Mills CO. Clare, Ireland

Re: K161508

Trade/Device Name: Ceruloplasmin Regulation Number: 21 CFR 866.5210 Regulation Name: Ceruloplasmin Immunological Test System Regulatory Class: II Product Code: DDB Dated: November 28, 2016 Received: December 8, 2016

Dear Ms. Sweeney:

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.

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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

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Sincerely yours,

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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) K161508

Device Name Ceruloplasmin

Indications for Use (Describe)

System reagent for the quantitative determination of Ceruloplasmin (CER) in human serum and plasma on Beckman Coulter AU analyzers as an aid in the diagnosis of copper metabolism disorders.

Type of Use (Select one or both, as applicable)
-------------------------------------------------	--

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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510k Summary Ceruloplasmin Reagent

1.0 Submitted By:

Marguerita Sweeney Regulatory Affairs Manager Beckman Coulter Ireland, Inc. Lismeehan, O'Callaghan's Mills Co. Clare, Ireland Telephone: +353-65-683-1495 Fax: +353-65-683-1122 Email: msweeney@beckman.com

2.0 Date of preparation:

May 26th 2016

3.0 Device Identification:

Proprietary Names: Ceruloplasmin Common Name: Ceruloplasmin Classification: 866.5210 Product Code: DDB

4.0 Predicate Device:

Candidate(s)	Predicate	Manufacturer	Docket Number
Ceruloplasmin	N Antisera to HumanCeruloplasmin	Siemens (formerlyDade-Behring)	K053074

The Ceruloplasmin reagent is substantially equivalent to the product listed above currently in commercial distribution

5.0 Description:

The Ceruloplasmin reagent is designed for optimal performance on the Beckman Coulter AU analyzers.

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6.0 Intended Use:

System reagent for the quantitative determination of Ceruloplasmin (CER) in human serum and plasma on Beckman Coulter AU analyzers as an aid in the diagnosis of copper metabolism disorders.

Clinical Significance

Ceruloplasmin's main clinical importance is in the diagnosis of Wilson's disease. Increased levels of Ceruloplasmin are particularly notable in diseases of the reticuloendothelial system such as Hodgkin's disease and also during pregnancy or use of contraceptive pills. Low levels of ceruloplasmin are found in malnutrition, malabsorption, nephrosis and severe liver disease particularly biliary cirrhosis.

7.0 Comparison to Predicate(s):

The following tables shows similarities and differences between the predicate identified in Section 4.0 of this summary.

Similarities
Feature	Ceruloplasmin reagent	Predicate
Intended Use	System reagent for thequantitative determination ofCeruloplasmin (CER) in humanserum and plasma on BeckmanCoulter AU analyzers as an aid inthe diagnosis of coppermetabolism disorders.	In-vitro diagnostic reagents for thequantitative determination ofceruloplasmin and hemopexin inhuman serum and heparanisedplasma by means ofimmunonephelopetry on the BN IIand BN Prospec ® system.
Measurement	Quantitative	Quantitative
Reagent	Liquid, Ready to use	Liquid, Ready to use
Calibration	Serum Protein Multi-calibrator(ODR3023) which is traceable toIFCC CRM470	N Protein Standard(OQIMG13E0502) which istraceable to ERM470
ReagentStorage/ClosedShelf Life	2-8°C until expiration date	2-8°C until expiration date
Linearity Range	60 - 2000 mg/L	Ceruloplasmin:0.07 - 2.2 g/L for a sample dilutionof 1:20.
Composition	Rabbit anti-human CeruloplasminantiserumSolution of polymers in Trisbuffer (pH 7.4-7.6)Preservatives - Sodium Azide &	Rabbit anti-human CeruloplasminantiserumPreservatives - Sodium Azide

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	Gentamicin
Specimen Type	Serum and Plasma (SodiumHeparin and Lithium Heparin)	Serum and heparinized plasma
Expected Values	200 - 600 mg/L	Ceruloplasmin: 0.2-0.6g/L (200-600mg/LHemopexin: 0.5 - 1.15g/L (500-1150mg/L)

Differences
Feature	Ceruloplasmin reagent	Predicate
Assay Methodology/Operating principle	Immunoturbitimetric	Immunonephelometry
Instrumentation	Beckman Coulter AU ClinicalChemistry analyzers	Siemens BN II and BN Prospec® Systems
Reagent On-boardStability	90 days	3 days
Calibration Frequency	14 days	Not specified
Interfering Substances	Bilirubin:No significant interference(≤10%) up to 40mg/dL	Bilirubin:No interference up to 0.6g/L
	Hemolysis:No significant interference(≤10%) up to 500 mg/dL	Hemolysis:No interference up to 10g/L
	Triglyceride:No significant interference(≤10%) up to 1000mg/dL	Triglyceride:No interference up to 2.4g/L
	Rheumatoid Factor (RF):No significant interference(≤10%) up to 500 IU/mL
Sensitivity	≤6mg/dL (60mg/L)	Established by lower limit ofreference curve - depends onthe concentration of proteins inthe N protein standard SL

8.0 Summary of Performance Data:

The data in the Premarket Notification on safety and effectiveness supports a finding of substantial equivalence to a predicate chemistry test systems already in commercial distribution. Equivalence is demonstrated through performance characteristics testing. Experiments included: Method comparison, Precision, Linearity, Sensitivity, Interferences, Stability and Expected Values, Prozone (Hook effect) and Auto-dilution.

Performance on method comparison and precision are summarized below:

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Method Comparison Study Results

Reference	Test	SampleRange:	Specifications	Results	Pass/Fail
Siemens(OUIEG09E0504)	Ceruloplasmin(OSR6x64)	Ref:108 mg/L-1890 mg/LTest:98 mg/L -1880 mg/L	Slope:0.900-1.100	Slope:1.056	Pass
			Intercept:≤ ± 30mg/L	Intercept:-26.10mg/L	Pass
			r: ≥0.975	0.990	Pass
			N:≥100	120	Pass

Precision Study Results

Sample	Concentrationmg/L	Within Run Precision			Total Precision			Pass/Fail
		%CV	SD	Specification	%CV	SD	Specification
Pool 1	95.99	1.10	1.042	≤5% CV orSD ≤1 mg/dL(10mg/L)	6.7	6.44	≤10% CV orSD ≤2 mg/dL(20mg/L)	Pass
Pool 2	148.36	1.10	1.70	≤5% CV orSD ≤1 mg/dL(10mg/L)	2.80	4.09	≤10% CV orSD ≤2 mg/dL(20mg/L)	Pass
Pool 3	254.17	0.90	2.30	≤5% CV orSD ≤1 mg/dL(10mg/L)	2.20	5.70	≤10% CV orSD ≤2 mg/dL(20mg/L)	Pass
Pool 4	596.43	0.90	5.46	≤5% CV orSD ≤1 mg/dL(10mg/L)	1.90	11.36	≤10% CV orSD ≤2 mg/dL(20mg/L)	Pass
Pool 5	915.61	0.7	6.78	≤5% CV orSD ≤1 mg/dL(10mg/L)	1.6	14.51	≤10% CV orSD ≤2 mg/dL(20mg/L)	Pass
Pool 6	1791.94	0.5	9.52	≤5% CV orSD ≤1 mg/dL(10mg/L)	1.4	25.23	≤10% CV orSD ≤2 mg/dL(20mg/L)	Pass

This summary of safety and effectiveness is being submitted in accordance with the requirements of the Safe Medical Device Act of 1990 and the implementing regulation 21 CFR 807.92

Regulation Number and Section

§ 866.5210 Ceruloplasmin immunological test system.

(a)
Identification. A ceruloplasmin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the ceruloplasmin (copper-transporting serum protein) in serum, other body fluids, or tissues. Measurements of ceruloplasmin aid in the diagnosis of copper metabolism disorders.(b)
Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.