The Direct Bilirubin test system is a device intended for the quantitative in vitro determination of Direct Bilirubin in serum and plasma. Bilirubin measurements can be used in the diagnosis and treatment of liver, hematological and metabolic disorders including hepatitis and gall bladder block.

This device is for prescription use only.

Device Description

The Randox Direct Bilirubin kit consists of ready to use reagent solutions.

CATALOGUE NUMBER: BR8308 COMPONENTS: R1. 4 x 20ml, R2. 4 x 8ml

REAGENT COMPOSITION

R1. Direct Bilirubin RI Tartrate buffer, pH2.9 Detergent Antimicrobials and Preservatives Inhibitors Initial Concentration of Solutions 0.1 mol/L
R2. Direct Bilirubin R2 Phosphate buffer, pH 7.0 Sodium Metavanadate Initial Concentration of Solutions 10 mmol/L 4 mmol/L

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the Randox Direct Bilirubin device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document provides performance characteristics but does not explicitly state "acceptance criteria" in a tabulated format derived from a regulatory body or a specific standard with pass/fail thresholds. Instead, it presents the results of various analytical performance studies. However, some sections imply acceptance criteria through their phrasing (e.g., "deviation from linearity is less than 5%" for linearity, "no significant interference" for specificity, and "≤20% CV imprecision" for LoQ).

Here's an interpretation of implied acceptance criteria and reported performance:

Acceptance Criteria (Implied)	Reported Device Performance
Precision/Reproducibility: Repeatability and intermediate precision within acceptable limits.	Serum Pool 1 (Mean 0.65 mg/dl): Within Run CV: 3.0%, Among Run CV: 1.6%, Among Day CV: 2.4%, Total CV: 4.2% Serum Pool 2 (Mean 2.31 mg/dl): Within Run CV: 3.1%, Among Run CV: 0.0%, Among Day CV: Not reported (likely very low, as next cell is blank), Total CV: 3.1% Serum Pool 4 (Mean 8.41 mg/dl): Within Run CV: 1.5%, Among Run CV: 0.8%, Among Day CV: 0.9%, Total CV: 1.9%
Linearity/Reportable Range: Linear function to analyte concentration (deviation from linearity < 5%).	Linearity: 0.1 - 12.6 mg/dl. Slope: 1.01, Intercept: -0.07, r: 0.9995, Syx: 0.10. Reportable Range: 0.1 - 12.6 mg/dl (with auto-dilution for >12.6 mg/dl).
Detection Limit (LoQ): Lowest concentration detectable with ≤20% CV imprecision.	LoD: 0.064 mg/dl LoB: 0.006 mg/dl LoQ: 0.133 mg/dl (confirmed to be ≤20% CV imprecision).
Analytical Specificity/Interference: No significant interference from common interferents at specified levels (Ac-ceptance Criteria: % of Control ± 10%).	Haemoglobin: No significant interference up to 1000 mg/dl Triglycerides: No significant interference up to 750 mg/dl Intralipid®: No significant interference up to 1000 mg/dl Ascorbic Acid: No significant interference up to 25 mg/dl (This suggests the results fell within ± 10% of the control).
Method Comparison with Predicate Device: Strong correlation with the predicate device.	Correlation Coefficient (r): 0.997 (for 103 serum patient samples spanning 0.123-12.46 mg/dl). Regression Equation: Y = 1.01x + 0.01.
Matrix Comparison: Agreement between serum and lithium heparin plasma samples.	Correlation Coefficient (r): 1.00 (for a minimum of 40 matched patient sample pairs spanning 0.091-12.48 mg/dl). Regression Equation: Y = 0.99x + 0.01.

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

Precision/Reproducibility:
- Sample Size: Not explicitly stated as a number of samples but rather as "control material and unaltered human serum samples" divided into pools (Pool 1, 2, 4) and tested over 20 non-consecutive days with 2 replicates per run. This implies a significant number of measurements for each pool.
- Data Provenance: "unaltered human serum samples." The country of origin is not specified, but the submission is from the UK. The study is prospective in nature (testing conducted for the device).
Linearity/Assay Reportable Range:
- Sample Size: Samples prepared at 11 levels. Each level run in replicates of five.
- Data Provenance: Not specified, but samples were prepared to cover a range of analyte concentrations. Prospective.
Detection Limit:
- Sample Size: 240 determinations (for LoD) with 4 low-level samples.
- Data Provenance: Not specified. Prospective.
Analytical Specificity/Interference:
- Sample Size: Not explicitly stated as a number of samples, but "the analytes detailed below were tested up to the levels indicated at Bilirubin concentrations of 0.14mg/dl and 5.03mg/dl."
- Data Provenance: Not specified. Prospective.
Method Comparison with Predicate Device:
- Sample Size: 103 serum patient samples.
- Data Provenance: "patient samples." The country of origin is not specified. Likely retrospective, as existing patient samples were used, but the testing itself was prospective.
Matrix Comparison:
- Sample Size: A minimum of 40 matched patient sample pairs.
- Data Provenance: "Patient samples." The country of origin is not specified. Likely retrospective, as existing patient samples were used, but the testing itself was 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 (IVD) test for quantitative determination of Direct Bilirubin. The "ground truth" for such devices is typically established through reference methods or established predicate devices, not through expert consensus in the same way an imaging or pathology AI might.

Precision, Linearity, Detection Limit, Specificity: Ground truth is inherent in the analytical methods themselves (e.g., gravimetric dilutions for linearity, spiked samples, controlled interferent concentrations). No external experts are mentioned.
Method Comparison and Matrix Comparison: The ground truth for these studies is the measurement obtained by the predicate device (Wako Direct Bilirubin V, K053132) or the matched serum/plasma results themselves. No external experts are described as establishing this "ground truth."

4. Adjudication Method for the Test Set

Not applicable for this type of IVD device. Adjudication is typically used in studies involving human interpretation (e.g., radiology reads) to resolve discrepancies.

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 automated in vitro diagnostic test, not an AI-assisted human reading device.

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 Randox Direct Bilirubin assay system, an automated IVD device. The results reported are directly from the instrument measurements.

7. The Type of Ground Truth Used

For analytical performance studies (Precision, Linearity, Detection Limit, Specificity): The 'ground truth' is established through controlled laboratory preparations (e.g., known concentrations of analytes, spiked samples, dilutions) and comparisons to established analytical methods as described in CLSI guidelines.
For method comparison: The 'ground truth' is the predicate FDA-cleared device (Wako Direct Bilirubin V, K053132).
For matrix comparison: The 'ground truth' is the serum sample measurement when comparing to lithium heparin plasma.

8. The Sample Size for the Training Set

Not applicable. This is a chemical assay, not a machine learning model that requires a training set. The "development" or "optimization" phase of such an assay would involve internal R&D, but it's not a "training set" in the context of AI/ML.

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

Not applicable. There is no training set for an IVD chemical assay as described here. Parameter settings and reagent formulations are determined through standard chemical and biochemical R&D processes, not through machine learning ground truth establishment.

Summary

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

RANDOX LABORATORIES LIMITED PAULINE ARMSTRONG, SENIOR MANAGER QA/RA 55 DIAMOND ROAD, CRUMLIN COUNTY ANTRIM BT29 4QY GREAT BRITAIN

February 16, 2016

Re: K152343

Trade/Device Name: Direct Bilirubin Regulation Number: 21 CFR 862.1110 Regulation Name: Bilirubin (total or direct) test system Regulatory Class: II Product Code: JFM Dated: January 04, 2016 Received: January 06, 2016

Dear Pauline Armstrong:

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

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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.

Katherine Serrano -S

Courtney H. Lias, Ph.D. For:

Director Division of Chemistry and Toxicology 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) K152343

Device Name Direct Bilirubin

Indications for Use (Describe)

This device is for prescription use only.

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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510(K) SUMMARY, DIRECT BILIRUBIN REAGENT

1. SAFETY AND EFFECTIVENESS AS REQUIRED BY 21 CFR 807.92 STATEMENT
  This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirement 21 CFR 807.92.

2. SUBMITTER NAME AND ADDRESS

Name: Dr Pauline Armstrong Address: Randox Laboratories Limited 55 Diamond Road, Crumlin, County Antrim, BT29 4QY, United Kingdom
Telephone: +44 (0) 28 9442 2413 Fax: +44 (0) 28 9445 2912 E-mail: Pauline.Armstrong@randox.com

Date of Summary Preparation: Feb 10, 2016

1. 510k NUMBER, DEVICE PROPRIETARY NAME, COMMON NAME, PURPOSE FOR SUBMISSION, REGULATORY CLASSIFCATION, PANEL, PRODUCT CODE AND 21 CFR NUMBER
  510k No.: K152343 Device Proprietary Name: Direct Bilirubin Common Name: Direct Bilirubin Purpose for Submission: New Device

ProductCode	Regulation Name	Classification	Regulation Section	Panel
JFM	Bilirubin (total ordirect) test system	II	21 CFR 862.1110	ClinicalChemistry (75)

4. PREDICATE DEVICE PROPRIETARY NAMES AND 510(k) NUMBERS

Predicate Device Proprietary Name: Wako Direct Bilirubin V 510(k) No .: K053132 Cataloque numbers: 02188390 & 02189494

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5. INTENDED USE

The Direct Bilirubin test system is a device intended for the quantitative in vitro determination of Direct Bilirubin in serum and plasma. Bilirubin measurements can be used in the diagnosis and treatment of liver, hemolytic, hematological and metabolic disorders including hepatitis and gall bladder block. This device is for prescription use only.

6. DEVICE DESCRIPTION

The Randox Direct Bilirubin kit consists of ready to use reagent solutions.

CATALOGUE NUMBER: BR8308 COMPONENTS: R1. 4 x 20ml, R2. 4 x 8ml

REAGENT COMPOSITION

Contents		Initial Concentrationof Solutions
RI.	Direct Bilirubin RITartrate buffer, pH2.9DetergentAntimicrobials and PreservativesInhibitors	0.1 mol/L
R2.	Direct Bilirubin R2Phosphate buffer, pH 7.0Sodium Metavanadate	10 mmol/L4 mmol/L

MATERIALS REQUIRED BUT NOT PROVIDED

Randox Assayed Multisera Level 2 (Cat. No. HN1530) and Level 3 (Cat. No. HE1532); 510(k) # K942458 Randox Calibration Serum Level 3 (Cat. No. CAL2351): 510(k) # K053153 RX series Saline (Cat.No. SA8396)

7. PREDICATE DEVICE COMPARISON TABLE Table 1 Comparison of Direct Bilirubin test system for the RX Daytona plus to predicate device

CHARACTERISTICS	Randox Direct Bilirubin Assay for RXDaytona Plus (New Device)	Direct Bilirubin (K053132)(Predicate Device)
SIMILARITIES
INTENDED USE	The Direct Bilirubin test system is a deviceintended for the quantitative in vitrodetermination of Direct Bilirubin in serum andplasma. Bilirubin measurements can be usedin the diagnosis and treatment of liver,haemolytic, haematological and metabolicdisorders including hepatitis and gall bladderblock. This device is for prescription use only.	Same
SAMPLE TYPE	SerumPlasma (Li Heparin)	Same
ASSAY PROTOCOL	Vanadate Oxidation Method	Same

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CHARACTERISTICS	Randox Direct Bilirubin Assay for RX Daytona Plus (New Device)	Randox Direct Bilirubin (K053132) (Predicate Device)
DIFFERENCES
STORAGE(UNOPENED)	Reagents are stable up to the expiry datewhen stored unopened at +2 to +8°C.	2-10°C
CALIBRATIONFREQUENCY	A two point calibration is recommended every28 days.	Recommended every 30 days.
CONTROLFREQUENCY	Two levels of control should be assayed atleast once a day	At least two levels of control should beassayed once a day, or change of lot
On-board Stability	On board stability has been determined as 28days.	On board stability has been determinedas 30 days.
REAGENTCOMPOSITION	R1. Direct BilirubinTartrate Buffer, pH2.9, 0.1mol/lDetergentAntimicrobials and PreservativesInhibitorsR2. Direct BilirubinPhosphate Buffer, pH7.0, 10mmol/lSodium Metavanadate, 4mmol/l	R1.Tartrate Buffer, pH2.9, 0.1mol/lDetergentR2.Phosphate Buffer, pH7.0, 10mmol/lSodium Metavanadate, 4mmol/l

8. Test Principle

The bilirubin is oxidised by vanadate at approximately pH3.0 to produce biliverdin. In the presence of detergent and vanadate, conjugate (direct) bilirubin is oxidised. This oxidation reaction causes a decrease in the optical density of the yellow colour, which is specific to bilirubin. The decrease in optical density at 450/546nm is proportional to the direct bilirubin concentration in the sample. The concentration is measured as an endpoint reaction.

Conjugated Bilirubin + VO3-

Tokuda K, Tanimoto K. New method of measuring serum bilirubin using vanadic acid. Jpn J Clin Chem. 1993:22:116-122.

9. PERFORMANCE CHARACTERISTICS

Analytical performance

a) Precision/Reproducibility

Precision was evaluated consistent with C.L.S.I standard EP5-A2. Precision studies were performed by two operators, on two RX Daytona plus systems using control material and unaltered human serum samples that were spiked with direct bilirubin concentrations or diluted to achieve concentrations based on established ranges up to 0.2mg/dl. Testing was conducted for two reagent lots of direct bilirubin, one lot on each RX Daytona plus system, twice per day for 20 non-consecutive days. Two replicates per run were performed for each sample. - No assay recalibrations were required throughout the duration of the study. The results are summarized in the following tables.

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System: Rx Daytona Plus				Within Run Amonq Run		Among Day		Total
Method	Product	MEAN	SD	CV	SD	CV	SD	CV	SD	CV
DBIL	Serum Pool 1	0.65	0.02		3.0 0.01	1.6	0.02	2.4	0.03	4.2
DBIL	Serum Pool 2	2.31	0.07		3.1 0.00	0.0	0.01		0.4 0.07	3.1
DBIL	Serum Pool 4	8.41	0.13		1.5 0.07	0.8	0.07	0.9	0.16	1.9

Table 1 Precision Summary - Lot 2

b) Linearity/assay reportable range

Linearity studies have been carried out in accordance with C.L.S.I. standard EP6-A. - Linearity studies were performed at 11 levels to determine the analytical range of an assay - that is the range where the reported result is a linear function to the analyte concentration (or where deviation from linearity is less than 5%).

The linearity samples were prepared at 11 levels. The sponsor set a range from 0.1mq/dl analyte concentration up to a high concentration approximately 12.6mg/dl. Each level was run in replicates of five on two lots of direct bilirubin reagent on one RX Daytona plus system. The results are summarized in the following table:

Table 3 Linearity Summary including regression equation and correlation coefficient

Slope	1.01
Intercept	-0.07
r	0.9995
Syx	0.10

Table 4 Linearity Summary

Analyte	Linearity	Reportable Range
Direct Bilirubin	12.6mg/dl	0.1-12.6mg/dl

The Rx Daytona Plus analyser has an auto-dilution feature that is automatically activated when measuring samples >12.6mg/dl. Samples >12.6mg/dl are diluted and re-measured to obtain values within the measuring range.

Traceability, Stability, Expected values (controls, calibrators, or C) methods)
Refer to 510(k) K053153 for Calibrator and K942458 Control information for Direct Bilirubin.

Randox Calibration Serum Level 3 is traceable to an internal master calibrator for Direct Bilirubin.

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d) Detection limit

Sensitivity studies have been carried out in accordance with C.L.S.I. guideline EP17-A2 'Protocols for Determination of Limits of Detection and Limits of Quantification; Approved Guideline'. A Limit of Blank (LoB), a Limit of Detection (LoD) and a Limit of Quantification (LoQ) were performed on two lots of reagents tested by two operators on one RX Davtona Plus svstem.

The LoD for Direct Bilirubin on the RX Daytona Plus is 0.064mg/dl based on 240 determinations, with 4 low level samples.

The LoB is 0.006mg/dl.

The LoQ is 0.133mg/dl as determined by the lowest concentration that can be detected with ≤20% CV imprecision.

e) Analytical Specificity

Interference studies have been carried out in accordance with C.L.S.I guideline EP7-A2 'Interference Testing in Clinical Chemistry; Approved Guideline Second Edition'. The effects of potential interferents were determined by calculating the mean value of the spiked interferent with the corresponding control solution. The spiked sample results were compared to control samples prepared without the potential interferents.

Acceptance Criteria: % of Control ± 10%

The analytes detailed below were tested up to the levels indicated at Bilirubin concentrations of 0.14mg/dl and 5.03mg/dl, and found not to interfere:

Haemoglobin	No significant interference up to 1000mg/dl
Triglycerides	No significant interference up to 750mg/dl
Intralipid®	No significant interference up to 1000mg/dl
Ascorbic Acid	No significant interference up to 25mg/dl

Table 5 Interference Summary

Method comparison with predicate device f)

Correlation studies were carried out in accordance with C.L.S.I. guideline EP9-A2 'Method Comparison and Bias Estimation Using Patient Samples: Approved Guideline - Second Edition'.

103 serum patient samples spanning the range 0.123-12.46mg/dl were tested by two operators on two lots of direct bilirubin reagent on a RX Daytona plus analyzer and a Siemens Advia system across 3 working days with each sample tested in singlicate. The test method was compared to the predicate device and the following linear regression equation was obtained:

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Y = 1.01x + 0.01 Correlation coefficient of r = 0.997

g) Matrix comparison

Matrix method comparisons for the direct bilirubin assay was tested by one operator on one RX Daytona plus system and was assessed for two lots of direct bilirubin reagents. Both serum and lithium heparin plasma were tested to determine whether method accuracy with lithium heparin specimens are equivalent to serum results and that lithium heparin plasma does not interfere with either the method or the system.

Direct bilirubin matrix comparison on the RX Daytona plus (Lithium Heparin) Patient samples were drawn in matched pairs – one sample serum (x) and the second sample lithium heparin plasma (y). A minimum of 40 matched patient sample pairs were analyzed spanning the range 0.091-12.48mg/dl and the following linear regression equation was obtained:

Y = 0.99x + 0.01 Correlation coefficient of r = 1.00

10. CONCLUSION

Testing results indicate that the proposed device is substantially equivalent to the predicate device.

Regulation Number and Section

§ 862.1110 Bilirubin (total or direct) test system.

(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.