Lumipulse G CA19-9-N is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of CA19-9 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System.

The assay is to be used as an aid in the management of patients diagnosed with cancer of the exocrine pancreas who have detectable levels of CA19-9 at some point in their disease process. Serial testing for patient CA19-9 assay values should be used in conjunction with other clinical methods used for monitoring cancer of the exocrine pancreas.

WARNING: The concentration of CA19-9 in a given specimen, as determined by assays from different manufacturers, can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the assay for CA 19-9 used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used for determining serial levels of CA 19-9 is changed, the laboratory must perform additional serial testing to confirm baseline values. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored. Lumipulse & CA19-9-N should not be used for cancer screening or diagnosis.

WARNING: Patients known to be genotypically negative for the Lewis blood group antigen will be unable to produce the CA19-9 antigen even in the presence of malignant tissue. Phenotyping for the Lewis antigen may be insufficient to detect true Lewis antigen negative individuals. Even patients who are genotypically positive for the Lewis antigen may produce varying levels of CA19-9 based on gene dosage effect.

Device Description

The Lumipulse G CA19-9-N Immunoreaction Cartridges (cat. # 235126) consists of 3 x 14 tests. Each kit contains the following:

Antibody-Coated Particle Solution (Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µg/mL anti-CA19-9 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15 °C or lower. Preservative: sodium azide.
Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.5 µq/mL alkaline phosphatase (ALP: calf)-labeled anti-CA19-9 monoclonal antibody (mouse), protein stabilizers (bovine, calf, and mouse) and chemical stabilizers in 0.05 M sodium chloride/Bis-Tris buffer. Preservative: sodium azide.

AI/ML Overview

The provided text describes the analytical and clinical performance of the Lumipulse G CA19-9-N device, a chemiluminescent enzyme immunoassay for the quantitative measurement of CA19-9 in human serum or plasma.

Here's an analysis of the acceptance criteria and study data:

Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a codified table for each test, but rather presents the study results and implicitly demonstrates that the device's performance metrics meet internal or regulatory thresholds for clearance. Based on the provided performance characteristics, the following can be inferred as acceptance criteria and the corresponding reported performance:

Performance Characteristic	Acceptance Criteria (Inferred)	Reported Device Performance
Analytical Performance
20-Day Precision (Total %CV)	≤ 5.3% (typical for assays around the measuring range)	≤ 5.3% (Panel 1)
Site-to-site Precision (Total %CV)	≤ 11.3% (typical for multi-site studies)	≤ 11.3% (Panel 1)
Lot-to-Lot Precision (Total %CV)	≤ 7.3% (typical for lot variability)	≤ 7.3% (Panel 1)
Linearity Range	Linear correlation across the measuring range	0.7 to 531.3 U/mL ($R^2=0.9983$)
Spike Recovery	100% ± 10% of expected value	95% to 109%
Measuring Range	Defined range of accurate measurement	0.7 U/mL to 500 U/mL
Limit of Blank (LoB)	Very low value, close to zero	0.10 U/mL
Limit of Detection (LoD)	Very low value, slightly above LoB	0.19 U/mL
Functional Sensitivity (LoQ)	Low value, indicating reliable low-end measurement	0.57 U/mL
Interfering Substances	Average interference ≤ 10%	Average interference ≤ 10% for all tested compounds
High Dose Hook Effect	No hook effect observed at very high concentrations	No hook effect observed up to 200,000 U/mL
Specimen Stability (Refrigerated)	Stable for up to 4 days	Stable for up to 4 days (2-10°C)
Specimen Stability (Frozen)	Stable for up to 14 days	Stable for up to 14 days (-20°C ±10°C)
Specimen Stability (On-board)	Stable for at least 3 hours	Stable for up to 3 hours
Manual Dilution	Recommend 1:10, 1:100, 1:200	Recommended 1:10, 1:100, 1:200
Automated Dilution	Recommend 1:10, 1:100, 1:200 for samples up to 80,000 U/mL	Recommended 1:10, 1:100, 1:200 for samples up to 80,000 U/mL
Matrix Comparison	Equivalency between matrices (serum, plasma types)	Demonstrated equivalency via high Pearson Correlation Coefficients (e.g., 0.9943 to 0.9981) and slopes/intercepts close to 1/0
Clinical Performance
Total Concordance (Serial Monitoring)	At least 61% (for aid in management)	61.23%
Sensitivity (Serial Monitoring)	At least 64%	64.29%
Specificity (Serial Monitoring)	At least 60%	60.53%

Study Details:

This document focuses on the analytical performance and clinical utility for an in vitro diagnostic (IVD) device, specifically an immunoassay for CA19-9. It does not describe a typical image-based AI/CADe/CADx study, therefore, many of the typical questions for such studies (e.g., number of experts, adjudication method, MRMC studies, standalone performance, training set details) are not applicable (N/A) in this context.

Here's a breakdown of the information available for this IVD device:

Sample sizes used for the test set and the data provenance:
- 20-Day Precision: 6 native human serum-based panels, tested in replicates of two separate times per day for 20 non-consecutive days (n=80 for each sample).
- Site-to-Site Precision: 6 serum samples, assayed in triplicate per run with two runs per day across five non-consecutive days for a total of ten runs per site (n=30 replicates per site). Tested at an internal lab and two additional sites.
- Lot-to-Lot Precision: 6 native serum samples, assayed in triplicate per run with 2 runs per day across 5 non-consecutive days for a total of 10 precision runs per lot (n=30 replicates per lot, 90 replicates per Panel across all three lots). Tested at the internal laboratory.
- Linearity: High and low sample pools created using patient serum samples.
- Spike Recovery: 3 normal human serum specimens.
- Detection Limit: 2 blank and 7 low-level serum specimens, tested in replicates of ten over 3 days on 2 LUMIPULSE G1200 Systems with 2 runs per day and 2 Lumipulse G CA19-9-N lots tested (60 determinations for each specimen per lot).
- Interfering Substances: Human serum specimen pools with three different CA 19-9 concentrations.
- High Dose Hook Effect: Samples containing approximately 200,000 U/mL of CA 19-9.
- Specimen Stability: Data derived from testing specimens under various storage conditions.
- Matrix Comparison: Fifty (50) matched sets of serum (red top and serum separator tubes (SST)) and plasma (K2EDTA, sodium heparin and lithium heparin) samples.
- Method Comparison: A total of 84 matched human serum samples. Later, 103 samples that required dilution were also included.
- Clinical Supportive Data (Monitoring): 83 patients, 374 pairs of observations, with an average of 5.6 observations per patient.
- Expected Values/Reference Range: 240 serum specimens from an "apparently healthy adult population" (22-93 years old).
- Disease Prevalence Studies (Contextual Data): 75 serum samples from patients with benign pancreatic conditions and 120 from patients with malignant pancreatic disease. Also, samples from patients with other benign conditions and other malignant conditions (e.g., Biliary, Breast, CRC, Gallbladder, Liver, Lung, Ovarian, Stomach cancer).
Data Provenance: Not explicitly stated regarding country of origin, but described as "native human serum-based panels," "patient serum samples," and "human serum specimens." The studies were performed at "internal laboratory," "external laboratory," and "two additional sites," suggesting clinical laboratory settings. The studies for 510(k) devices are typically retrospective, using banked clinical samples, though this is not explicitly stated as retrospective or prospective for all studies. The "Monitoring of Disease State" study with serial samples implies a prospective design in collecting follow-up data, but the collection itself might have been retrospective of existing patient records.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience):
- N/A. This is an IVD immunoassay, not an imaging device. Ground truth for most analytical performance studies is established by the known concentration of analytes in reference materials or by comparison to a legally marketed predicate device/method.
- For the "Monitoring of Disease State" study, the "disease status" (progression/no progression) serves as the ground truth. This would typically be established by a clinician's assessment based on various clinical methods and follow-up, but the number and qualifications of such clinicians are not specified in this document.
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- N/A. Not relevant for an IVD immunoassay.
Medical Reader Multi-Case (MRMC) comparative effectiveness study:
- N/A. This is not an AI/CADe/CADx device that assists human readers.
Standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, in essence. Diagnostic assays like this device operate standalone to produce a quantitative result. The device's performance is measured and reported directly (e.g., U/mL for CA19-9). The "human-in-the-loop" aspect is the clinician interpreting the result in conjunction with other clinical methods.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Analytical Performance: Ground truth is based on known concentrations for linearity, detection limits, spike recovery, and established reference methods (e.g., ARCHITECT CA 19-9XR as predicate) for method comparison.
- Clinical Supportive Data (Monitoring): The ground truth for correlating CA19-9 changes was "changes in disease status," defined as "disease progression" or "no progression." This "disease status" is typically determined by physician's assessment based on imaging, biopsies, clinical symptoms, and other diagnostic tests (i.e., outcomes data/clinical assessment), not pathology in itself for every observation.
The sample size for the training set:
- N/A. This is a traditional immunoassay, not a machine learning/AI device requiring a separate "training set" in the computational sense. The "training" of such a device primarily involves the development and optimization of the reagent formulation and assay parameters based on extensive R&D data, which is distinct from a machine learning training set.
How the ground truth for the training set was established:
- N/A. As above, not a typical AI/ML training set.

Summary

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October 22, 2019

Fujirebio Diagnostics, Inc. Kristin Maddaloni Regulatory Affairs Specialist 201 Great Valley Parkway Malvern, Pennsylvania 19355

Re: K191973

Trade/Device Name: Lumipulse G CA19-9-N Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-associated antigen immunological test system Regulatory Class: Class II Product Code: NIG Dated: July 22, 2019 Received: July 24, 2019

Dear Kristin Maddaloni:

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.

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

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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 (OS) 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 mediation-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.

Douglas Jeffery, Ph.D. Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K191973

Device Name Lumipulse G CA19-9-N

Indications for Use (Describe)

WARNING: The concentration of CA19-9 in a given specimen, as determined by assays from different manufacturers, can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the assay for CA19-9 used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used for determining serial levels of CA 19-9 is changed, the laboratory must perform additional serial testing to confirm baseline values. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored. Lumipulse & CA19-9-N should not be used for cancer screening or diagnosis.

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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Section 5 510(k) SUMMARY

A. GENERAL INFORMATION

Submission Date: July 22, 2019

Submitter Information:

Submitted By:

Fujirebio Diagnostics, Inc. 201 Great Valley Parkway Malvern, PA 19355

Contact Person:

Kristin Maddaloni Regulatory Affairs Specialist Fujirebio Diagnostics, Inc. 201 Great Valley Pkwy Malvern, PA 19355 Office: 484-395-2126 maddalonik@fdi.com

B. PURPOSE FOR SUBMISSION

To obtain a substantial equivalence determination for the Lumipulse G CA19-9-N.

C. MEASURAND

CA 19-9

D. TYPE OF TEST

Quantitative, Chemiluminescent Immunoassay

E. APPLICANT

Fujirebio Diagnostics, Inc.

F. PROPRIETARY AND ESTABLISHED NAMES

Lumipulse® G CA 19-9-N Lumipulse® G CA19-9-N Immunoreaction Cartridges

G. REGULATORY INFORMATION

Trade Name: Lumipulse G CA19-9-N Classification: Class II Regulation: 21 CFR 866.6010

Lumipulse G CA19-9-N

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Image /page/4/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic element on the left, consisting of blue and green shapes. To the right of the graphic is the company name, "FUJIREBIO," in a bold, blue sans-serif font, with the registered trademark symbol next to it. Below the company name is the text "Diagnostics, Inc." in a smaller, black sans-serif font.

Requlation Name: Tumor-Associated Antigen Immunological Test System Product Code: NIG - System, Test. Carbohydrate antigen (CA 19-9) for monitoring and management of pancreatic cancer Panel: 82, Immunology

H. INTENDED USE / INDICATIONS FOR USE

1. Intended Use / Indications for use
  Lumipulse® G CA19-9-N is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of CA 19-9 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System.

The assay is to be used as an aid in the management of patients diagnosed with cancer of the exocrine pancreas who have detectable levels of CA 19-9 at some point in their disease process. Serial testing for patient CA 19-9 assay values should be used in conjunction with other clinical methods used for monitoring cancer of the exocrine pancreas.

1. Warning statements:
  The concentration of CA 19-9 in a given specimen, as determined by assays from different manufacturers, can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the assay for CA 19-9 used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used for determining serial levels of CA 19-9 is changed, the laboratory must perform additional serial testing to confirm baseline values. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored. Lumipulse G CA19-9-N should not be used for cancer screening or diagnosis.

Patients known to be genotypically negative for Lewis blood group antigen are unable to produce the CA 19-9 antigen even in the presence of malignant tissue. Phenotyping for the presence of the Lewis blood group antigen may be insufficient to detect true Lewis antigen negative individuals. Even patients who are genotype positive for the Lewis antigen may produce varying levels of CA 19-9 as the result of gene dosage effect.

1. Special instrument requirements: Lumipulse G System

l. INDICATIONS FOR USE

Indicated for the serial measurement of CA 19-9 to aid in the management of patients diagnosed with cancers of the pancreas. Serial testing with Lumipulse® G CA19-9-N for CA 19-9 patient values is used in conjunction with other clinical methods in the management of pancreatic cancer patients.

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Image /page/5/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized graphic on the left and the company name on the right. The graphic is a combination of blue and green shapes, while the company name is written in blue and black. The word "FUJIREBIO" is in blue, and the words "Diagnostics, Inc." are in black.

J. DEVICE DESCRIPTION

Reagents

The Lumipulse G CA19-9-N Immunoreaction Cartridges (cat. # 235126) consists of 3 x 14 tests. Each kit contains the following:

1. Antibody-Coated Particle Solution (Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µg/mL anti-CA19-9 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15 °C or lower. Preservative: sodium azide.
1. Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.5 µq/mL alkaline phosphatase (ALP: calf)-labeled anti-CA19-9 monoclonal antibody (mouse), protein stabilizers (bovine, calf, and mouse) and chemical stabilizers in 0.05 M sodium chloride/Bis-Tris buffer. Preservative: sodium azide.

K. SUBSTANTIAL EQUIVALENCE INFORMATION

1. Predicate device name(s): ARCHITECT® CA 19-9TM xR Assay
1. Predicate 510(k) number(s): K052000
1. Comparison with predicate:

	Lumipulse® G CA19-9-N	ARCHITECT® CA 19-9TM XR(K052000) (Predicate)
Assay Intended Use	Lumipulse® G CA19-9-N is aChemiluminescent EnzymeImmunoassay (CLEIA) for thequantitative measurement of CA19-9 in human serum or plasma(sodium heparin, lithium heparin,or dipotassium EDTA) on theLUMIPULSE G System.The assay is to be used as an aidin the management of patientsdiagnosed with cancer of theexocrine pancreas who havedetectable levels of CA 19-9 atsome point in their diseaseprocess. Serial testing for patientCA19-9 assay values should beused in conjunction with otherclinical methods used for	The ARCHITECT® CA 19-9TM assay isa Chemiluminescent MicroparticleImmunoassay (CMIA) for thequantitative determination of 1116-NS-19-9 reactive determinants in humanserum and plasma on the ARCHITECTiSystem.The ARCHITECT® CA 19-9TM assay isto be used as an aid in the managementof pancreatic cancer patients with adetectable level of Ca 19-9 at somepoint in their disease process and inconjunction with other clinical methods.

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Image /page/6/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized graphic on the left and the company name on the right. The graphic is a combination of blue and green shapes, with a white teardrop shape in the center. The company name is written in blue, with "FUJIREBIO" in a larger font size than "Diagnostics, Inc."

	Lumipulse® G CA19-9-N	ARCHITECT® CA 19-9TM XR(K052000) (Predicate)
	monitoring cancer of the exocrine
	pancreas.
SIMILARITIES
Classification	Class II	Same
Product Code	NIG	Same
Regulation	21 CFR 866.6010	Same
Antibody Type andSource	monoclonal antibody (mouse)	Same
Sample Type	human serum and plasma	Same
Reagent Storage	Store at 2-10°C	Store at 2-8°C
Sample Size	100 μL	< 100 μL
CalibrationFrequency	Every 30 days	Same
	DIFFERENCES
Instrument	Lumipulse G System	ARCHITECT i System
Methodology	CLEIA	CMIA
Measuring Range	0.7-500 U/mL	2-1200 U/mL
Capture	Monoclonal anti-CA19-9 antibody(mouse)-coated particles	Monoclonal anti-CA 19-9 antibodycoated paramagnetic microparticles
Conjugate Antibody	ALP (calf)-labeled anti-CA19-9monoclonal mouse antibody	Acridinium labeled monoclonal anti-CA19-9 F(ab')2 conjugate
Calibrators	2 level set (1 vial/level):• Cal 1: 0 U/mL• Cal 2: 500 U/mL	6 level set:• Calibrator A: anti-microbial agent,protein stabilizers in TRIS buffer• Calibrator B-F: Recombinant human1116-NS-19-9 in TRIS buffer
Calibration Range	0-500 U/mL	0-1200 U/mL
Controls	2 levels every 24 hours	3 levels every 24 hours

L. STANDARDS/GUIDANCE DOCUMENTS REFERENCED

. CLSI EP05-A3 - Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
. CLSI EP06-A - Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline
. CLSI EP07 - Interference Testing in Clinical Chemistry; Approved Guideline - Third Edition
CLSI EP09-A3 – Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline - Third Edition
. CLSI EP14-A2 - Evaluation of Matrix Effects; Approved Guideline - Second Edition
CLSI EP17-A2 - Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition
CLSI EP25-A – Evaluation of Stability of In Vitro Diagnostic Reagents: Approved Guideline
. CLSI EP28-A3c - Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory: Approved Guideline-Third Edition

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CLSI EP34 - Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking; Approved Guideline - First Edition

M. TEST PRINICIPLE

Lumipulse® G CA19-9-N is an assay system, including a set of immunoassay reagents, for the quantitative measurement of CA 19-9 in human serum and plasma (sodium heparin, lithium heparin, or dipotassium EDTA) based on CLEIA technology by a two-step immunoassay method on the LUMIPULSE G1200 System. CA 19-9 in specimens specifically binds to anti-CA19-9 monoclonal antibody (mouse) on the particles, and antigenantibody immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Alkaline phosphatase (ALP: calf)-labeled anti-CA19-9 monoclonal antibody (mouse) specifically binds to CA 19-9 of the immunocomplexes on the particles, and additional immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Substrate Solution is added and mixed with the particles. AMPPD contained in the Substrate Solution is dephosphorylated by the catalysis of ALP indirectly conjugated to particles. Luminescence (at a maximum wavelength of 477 nm) is generate by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of CA 19-9.

N. PERFORMANCE CHARACTERISTICS

1. Analytical Performance

a. Reproducibility/Precision

20-Day Precision

The single site precision study was conducted using the Lumipulse G CA19-9-N at an external laboratory according to CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures. Six native human serum-based panels targeting the measuring range were assayed in replicates of two separate times of the day for 20 non-consecutive days (n=80 for each sample) using one LUMIPULSE G1200 System and one Lumipulse G CA19-9-N lot. Lumipulse G CA19-9-N demonstrated precision ≤5.3% (total %CV). Within-Laboratory (Total) precision combines Within-run, Between-run, and Between-day precision, and the results are presented below.

Sample	Mean(U/mL)	Within-Run(Repeatability)SD	Within-Run(Repeatability)%CV	Between RunWithin DaySD	Between RunWithin Day%CV	Between-DaySD	Between-Day%CV	Within-Laboratory(Total)SD	Within-Laboratory(Total)%CV
Panel 1	2.9	0.1	2.7%	0.0	1.6%	0.1	4.3%	0.2	5.3%
Panel 2	38.9	0.6	1.6%	0.4	1.0%	0.8	2.2%	1.1	2.9%
Panel 3	173.9	2.1	1.2%	1.3	0.8%	2.6	1.5%	3.6	2.1%
Panel 4	318.9	3.9	1.2%	3.3	1.0%	3.6	1.1%	6.3	2.0%
Panel 5	452.8	4.7	1.0%	3.3	0.7%	4.7	1.0%	7.5	1.6%
Panel 6	20.0	0.3	1.6%	0.3	1.3%	0.8	3.8%	0.9	4.3%

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Image /page/8/Picture/1 description: The image is a logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic on the left, consisting of blue and green shapes that resemble a water droplet or a stylized leaf. To the right of the graphic, the word "FUJIREBIO" is written in a bold, blue sans-serif font. Below "FUJIREBIO", the words "Diagnostics, Inc." are written in a smaller, lighter-weight sans-serif font.

Site-to-site Precision

The site-to-site precision studies were conducted using the Lumipulse G CA19-9-N at the internal laboratory and two additional sites according to CLSI EP05-A3. A panel of six serum samples targeting the measuring range were assayed in triplicate per run with two runs per day across five nonconsecutive days for a total of ten runs per site (n=30 replicates per site). Three different LUMIPULSE G1200 Systems were used for testing (one per site). The controls were tested in singlicate per run. This data was combined for site-to-site analysis. One Lumipulse G CA19-9-N Immunoreaction Cartridges lot and one Lumipulse G CA19-9-N Calibrator lot were used for testing. Lumipulse G CA19-9-N demonstrated precision ≤ 11.3% (total %CV). Within-Laboratory (Total) precision combines within-run, between-run and between-day precision, and data are presented below.

		BetweenSite		BetweenDay		BetweenRun		Within-Run(Repeatability)		Reproducibility(Total)
Sample	Mean(U/mL)	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	2.4	0.0	0.0%	0.1	2.3%	0.3	10.7%	0.1	2.6%	0.3	11.3%
Panel 2	33.8	0.4	1.0%	1.0	2.9%	1.7	5.2%	0.5	1.5%	2.1	6.2%
Panel 3	152.2	2.6	1.7%	4.0	2.7%	5.6	3.7%	1.5	1.0%	7.5	4.9%
Panel 4	280.5	5.1	1.8%	11.2	4.0%	7.9	2.8%	2.8	1.0%	14.9	5.3%
Panel 5	396.2	12.3	3.1%	13.1	3.3%	16.4	4.1%	3.9	1.0%	24.7	6.2%
Panel 6	17.3	0.2	0.9%	0.0	0.0%	1.3	7.6%	0.3	1.6%	1.3	7.8%

Lot-to-Lot Precision

The lot-to-lot study was conducted using three lots of Lumipulse G CA19-9-N Immunoreaction Cartridges and Calibrators at the internal laboratory according to CLSI EP05-A3. A panel of 6 native serum samples targeting the measuring range were assaved in triplicate per run with 2 runs per day across 5 nonconsecutive days for a total of 10 precision runs per lot (n=30 replicates per lot). There were 90 replicates per Panel across all three lots. Lumipulse G CA19-9-N demonstrated within total laboratory precision ≤ 7.3% (total %CV). The between-lot precision for Lumipulse G CA19-9-N was ≤ 6.1%.

		BetweenLot	BetweenDay		Between Run	Within-Run		WithinLaboratory(Total)
Sample	Mean(U/mL)	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	2.3	0.1	6.1%	0.1	2.2%	0.0	1.9%	0.1	2.7%	0.2	7.3%
Panel 2	34.6	0.3	0.7%	0.5	1.5%	0.5	1.5%	1.2	3.4%	1.4	4.1%
Panel 3	158.1	4.7	3.0%	0.0	0.0%	2.8	1.8%	1.7	1.1%	5.7	3.6%
Panel 4	290.6	10.1	3.5%	4.0	1.4%	6.1	2.1%	2.7	0.9%	12.8	4.4%
Panel 5	412.6	12.0	2.9%	6.9	1.7%	7.2	1.7%	4.4	1.1%	16.2	3.9%
Panel 6	17.1	0.4	2.4%	0.3	1.7%	0.2	1.0%	0.2	1.3%	0.6	3.4%

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Image /page/9/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo consists of a blue and green abstract shape on the left, followed by the company name in blue, bold letters. Below the company name, the words "Diagnostics, Inc." are written in a smaller, gray font.

b. Linearity

Linearity:

Lumipulse G CA19-9-N on the LUMPULSE G1200 System demonstrated linearity in a study consistent with the guidelines in the CLSI Protocol EP6-A, Evaluation of the Linearity of Quantitative Measurement Procedures. High and low sample pools were created using patient serum samples that contained naturally expressed CA 19-9. The linearity was found in the range 0.7 to 531.3 U/mL. Lumipulse G CA19-9-N correlated with expected concentrations per the linear regression formula:

y= -6.0810-2+1.10x-5.5810-4x2+7.85*10-7 x3; R2=0.9983

Dilution:

The recommended manual dilution for Lumipulse G CA19-9-N is 1:10, 1:100, and 1:200.

The recommended automated dilution for Lumipulse G CA19-9-N is 1:10, 1:100 and 1:200 for samples up to 80,000 U/mL. Automated dilutions for samples exceeding 80,000 U/mL is not recommended.

Spike Recovery:

Three normal human serum specimens with known endogenous CA 19-9 levels were split into 6 aliquots and spiked with various concentrations of CA 19-9 (50 U/mL, 150 U/mL, 250 U/mL, 375 U/mL and 450 U/mL). Aliquots were assayed in triplicate. The percent recovery was calculated. The percent recoveries ranged from 95% to 109%. The obtained percent recovery was between 100 ± 10% of the expected value for each spiked level. Therefore, the assay meets the acceptance criterion.

The assay measuring range is from 0.7 U/mL to 500 U/mL.

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

Expected Values:

Lumipulse G CA19-9-N Calibrators are for in vitro diagnostic use in the calibration of Lumipulse G CA19-9-N on the LUMIPULSE G System for the quantitative determination of CA 19-9 in human serum and plasma. Two bottles (1.5 mL each) are supplied for the Lumipulse G CA19-9-N Calibrator kit. Preservative: Sodium azide. The calibrators are at the following concentrations:

Calibrator	Concentration (U/mL)
CAL 1	0
CAL 2	500

Traceability:

Calibration of the Lumipulse G CA19-9-N is traceable to in-house reference calibrators, whose values have been assigned to correlate to Fujirebio Diagnostics' CA19-9 RIA.

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Shelf life:

The shelf life for Lumipulse G CA19-9-N Immunoreaction Cartridges and the Lumipulse G CA19-9 Calibrators is 12 months at 2-10°C.

On board the LUMIPULSE G1200:

The Lumipulse G CA19-9-N Immunoreaction Cartridges are sealed unit dose stored at 2–10°C. To reduce risk for any misuse, the package insert states "The Lumipulse G CA19-9 Immunoreaction Cartridges can be stored (refrigerated unit) on-board the LUMIPULSE G System for a maximum of 30 days".

The package insert recommends calibrator curve storage on the LUMIPULSE G1200 for a maximum of 30 days.

Transport Conditions:

Lumipulse G CA19-9-N Immunoreaction Cartridges and the Lumipulse G CA19-9 Calibrators are stable up to 12 months and are shipped at 2-10°C.

d. Detection Limit

The Limit of Blank (LoB), Limit of Detection (LoD), and Functional Sensitivity for the Lumipulse G CA19-9-N were determined in accordance with the CLSI Guideline EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures. Two blank and seven low level serum specimens were tested in replicates of ten over 3 days on 2 LUMIPULSE G1200 Systems with 2 runs per day and 2 Lumipulse G CA19-9-N lots were tested giving 60 determinations for each specimen per lot.

The LoB for Lumipulse G CA19-9-N on the LUMIPULSE G1200 System was determined to be 0.10 U/mL.

The LoD for Lumipulse G CA19-9-N on the LUMIPULSE G1200 System was determined to be 0.19 U/mL.

The LoQ was expressed through Functional Sensitivity; the lowest amount measured and detected by Lumipulse G CA19-9-N assay. The Functional Sensitivity was calculated to be 0.57 U/mL.

e. Analytical Specificity/Cross Reactivity

No data provided.

ﺖ Interfering Substances

The endogenous and exogenous interference studies followed the guidance of CLSI Guideline EP07, Interference Testing in Clinical Chemistry. Lumipulse G CA19-9-N on the LUMIPULSE G1200 System demonstrated an average interference of ≤10% for each compound shown in the table below. Human serum specimen pools with CA 19-9 concentrations of approximately 32.3 U/mL, 197.9 U/mL, and 344.7 U/mL were supplemented with potentially interfering compounds. The following compounds were

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Image /page/11/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. On the left is a blue and white abstract symbol. To the right of the symbol is the company name, "FUJIREBIO" in blue, with "Diagnostics, Inc." in a smaller, dark gray font below it.

tested using Lumipulse G CA19-9-N and found not to interfere with the assay.

Endogenous Interferences	Test Concentration
Free Bilirubin (unconjugated)	60 mg/dL
Conjugated Bilirubin	60 mg/dL
Triglycerides (Intralipid 20% Emulsion)	3,000 mg/dL
Hemoglobin	500 mg/dL
Hemoglobin	1000 mg/dL
Total Protein (Human Serum Albumin)	15 g/dL
Immunoglobulin G (IgG)	5 g/dL
Biotin	19.7 mg/dL
HAMA IgG	1000 ng/dL
RF IgM	1000 IU/mL
Therapeutic Drug Interferences	Test Concentration
5-Fluorouracil	39.0 mg/dL
Cisplatin	5.70 mg/dL
Cyclophosphamide	37.5 mg/dL
Cytarabine	3.0 mg/dL
Doxorubicin HCl	4.0 mg/dL
Gemcitabine	38.2 mg/dL
Leucovorin	11.4 mg/dL
Methotrexate	90.9 mg/dL
Paclitaxel	6.7 mg/dL
Pegylated Liposomal Doxorubicin (Doxil®)	5.2 mg/dL
Streptozotocin	3.96 mg/dL

g. High Dose Hook Effect

The Hook Effect was evaluated for the Lumipulse G CA19-9-N on the LUMIPULSE G1200 System. No high dose effect was observed for samples containing approximately 200,000 U/mL of CA 19-9.

h. Assay Cut-off

See Clinical Cut-off Section 3 below.

Specimen Stability ...

The following storage conditions were tested in the specimen stability studies and the results are as follows.

Specimens may be stored at refrigerated (2-10°C) for up to 4 days. .
Specimens may be stored frozen (-20°C ±10°C) for up to 14 days. ●
Specimens on-board the LUMIPULSE G System should be tested within 3 hours. ●
Avoid freezing or thawing samples. Do not perform freeze/thaw cycle 2 or more . times.
. Do not use heat inactivated specimens.

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Matrix Comparison j.

The Anticoagulant Matrix Comparison Study followed the guidance of the CLSI Guideline EP14-A2, Evaluation of Matrix Effects. Lumipulse G CA19-9-N on the LUMIPULSE G1200 System was evaluated for matrix differences by performing a study using fifty (50) matched sets of serum (red top and serum separator tubes (SST)) and plasma (K2EDTA, sodium heparin and lithium heparin) samples. The results demonstrated equivalency between matrices and are presented in the following table.

TubeType	n	ConcentrationRange(U/mL)	Slope			Intercept			PearsonCorrelationCoefficient
		Min	Max	Estimate	Lower95%CI	Upper95%CI	Estimate	Lower95% CI	Upper95% CI
SST	50	3.7	441.2	1.0094	0.9634	1.0553	0.7764	-3.0258	4.5785	0.9943
K2EDTA	50	4.2	456.0	1.0039	0.9860	1.0218	-0.1197	-0.4746	0.2352	0.9977
LithiumHeparin	50	4.8	430.3	0.9885	0.9605	1.0165	0.6344	0.0075	1.2614	0.9938
SodiumHeparin	50	3.9	470.2	0.9981	0.9746	1.0215	0.7679	-0.0781	1.6138	0.9981

k. Method Comparison

The Lumipulse G CA19-9-N Method Comparison Study followed the guidance of CLSI Document EP09-A3. Measurement Procedure Comparison and Bias Estimation Using Patient Samples and was performed on the LUMIPULSE G1200 System. The weighted Deming regression method was used to compare the performance of the Lumipulse G CA19-9-N to the ARCHITECT CA 19-9XR run on the ARCHITECT i System on a total of 84 matched human serum samples. The samples tested ranged from 3.0 to 454.8 U/mL for Lumipulse G CA19-9 and 2.07 to 1056.05 U/mL for ARCHITECT CA 19-9XR assay. The data are summarized in the following table.

	Lumipulse G CA19-9-N vs. ARCHITECT CA19-9XR
RegressionAnalysis	n	CorrelationCoefficient (r)	Intercept(95% CI)	Slope(95% CI)	Average Bias(U/mL)
WeightedDeming	84	0.6628	1.8650	1.3179	164.15%
			-0.9314 to 4.6615	1.0108 to 1.6250

The data summarized in the following table include results from a study with specimens above the measurement range of both devices requiring dilution (103 samples). The samples tested ranged from 3.0 to 1187.0 U/mL for Lumipulse G CA19-9-N and 2.07 to 1121.01 U/mL for ARCHITECT CA19-9XR.

Lumipulse G CA19-9-N vs. ARCHITECT CA19-9XR
n	CorrelationCoefficient (r)	Intercept(95% CI)	Slope(95% CI)	Average Bias(U/mL)
103	0.7380	1.8585	1.3198	143.45%
		-0.73934 to 4.4563	1.0780 to 1.15617

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Image /page/13/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized graphic on the left, followed by the company name in blue text. The graphic appears to be a combination of shapes and lines, with a mix of solid blue and striped teal elements. The text "FUJIREBIO" is in a larger, bolder font above "Diagnostics, Inc."

2. Clinical Studies

a. Clinical Sensitivity

Not Applicable.

b. Clinical Specificity

Not Applicable.

c. Other Clinical Supportive data:

Monitoring of Disease State in Patients Diagnosed with Pancreatic Cancer

The effectiveness of Lumipulse G CA19-9-N as an as an aid in the management of patients diagnosed with cancer of the exocrine pancreas who have detectable levels of CA 19-9 at some point in their disease process was determined on the LUMIPULSE G1200 System by assessing changes in CA 19-9 levels in serial serum samples from 83 patients compared to changes in disease status. A study involving a total of 374 pairs of observations was undertaken with an average number of 5.6 observations per patient. A positive change in CA 19-9 was defined as an increase in the value that was at least 15% greater than the previous value of the test. This level of change takes into account the variability of the assay. Sixty-five percent (65%) or 45/70 of the patient samples with a positive change correlated with the disease progression while sixtyone percent 61% or 184/304 of the patient serial samples with no significant change in CA 19-9 value correlated with no progression. The total concordance was sixty-one percent (61% or 229/374).

PerformanceMeasurement	Value	StandardError	Lower 95% CI*	Upper 95%Cl
Sensitivity	64.29	4.42	55.49	73.08
Specificity	60.53	2.48	55.60	65.45
Total Concordance	61.23	2.22	56.81	65.65
PPV	27.27	2.63	22.04	32.50
NPV	88.04	1.87	84.32	91.76

Lumipulse G CA19-9-N Performance Measurements (%)

*CI = Confidence Interval

The following table presents the data in a 2 x 2 format:

Change in Disease Status per Sequential Pair
----------------------------------------------	--	--	--

Change in CA 19-9 Concentration	No Progression	Progression	Total
< 15%	184	25	209
≥ 15%	120	45	165
Total	304	70	374

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Image /page/14/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized graphic on the left and the company name on the right. The graphic is a combination of blue and green shapes, while the company name is written in blue and black. The word "FUJIREBIO" is in blue, and the words "Diagnostics, Inc." are in black.

3. Clinical Cut-Off

See Expected Values below.

4. Expected Values/Reference Range

A total of 240 serum specimens obtained from an apparently healthy adult population (22-93 years old) were tested using the Lumipulse G CA19-9-N per CLSI EP28-A3c. The observed ranges are listed below.

	Apparently Healthy Malesand Females (Combined)	Apparently HealthyMales	Apparently HealthyFemales
N	240	120	120
Mean (SD)	11.0 (11.7)	10.5 (11.4)	11.5 (12.1)
Median	6.7	6.2	7.6
Range (min, max)	<0.7, 63.9	<0.7, 63.9	<0.7, 57.5
Reference Interval (2.5thPercentile, 97.5th Percentile)	<0.7, 50.0	<0.7, 40.1	<0.7, 50.6
N (%) with CA19-9 ≤25.0	88.8%	88.3%	89.2%
N (%) with CA19-9 ≤50.0	97.5%	98.3%	96.7%
N (%) with CA19-9 ≤75.0	100.0%	100.0%	100.0%

All Lumipulse G CA19-9-N concentrations are presented in U/mL.

In addition to the normal cohort, 75 serum samples from patients with benign pancreatic conditions and 120 from patients with malignant pancreatic disease were tested.

The following tables summarizes the sample distribution, diseases/conditions and distribution of CA 19-9 results. All Lumipulse G CA19-9-N concentrations are presented in U/mL.

	Pancreatitis	BenignLungDisease	BenignRenalDisease	Cirrhosis	Diabetes	GallbladderDisease	Hepatitis	RectalPolyps
N	75	39	40	38	40	41	42	40
Mean (SD)	58.2 (227.0)	31.9 (70.7)	21.9 (31.1)	33.3 (36.1)	15.4 (15.1)	45.3 (110.5)	32.4 (37.1)	20.0(26.2)
Median	18.5	13.8	12.6	20.6	9.9	12.0	21.6	8.8
Range (min,max)	<0.7, 1966.0	<0.7, 441.6	<0.7, 180.6	<0.7, 183.9	<0.7, 69.5	<0.7, 630.0	<0.7, 159.3	<0.7, 84.5
ReferenceInterval (2.5thPercentile,97.5thPercentile)	<0.7, 181.4	<0.7, 105.7	<0.7, 68.3	4.7, 120.9	<0.7, 56.0	<0.7, 334.2	<0.7, 151.6	<0.7, 83.7
N (%) withCA 19-9 ≤25.0	62.7%	71.8%	70.0%	57.9%	80.0%	68.3%	61.9%	80.0%
N (%) withCA 19-9 ≤50.0	84.0%	87.2%	90.0%	84.2%	95.0%	82.9%	78.6%	85.0%
N (%) withCA 19-9 ≤75.0	89.3%	89.7%	97.5%	89.5%	100.0%	90.2%	90.5%	87.5%

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Image /page/15/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic on the left, consisting of blue and green shapes. To the right of the graphic, the word "FUJIREBIO" is written in a bold, blue sans-serif font. Below "FUJIREBIO", the words "Diagnostics, Inc." are written in a smaller, gray sans-serif font.

	ExocrinePancreatic*	Biliary	Breast	CRC*	Gall-bladder	Liver	Lung	Ovarian	Stomach
N	120	40	40	38	40	40	40	39	37
Mean (SD)	2873.1(8721.0)	2640.0(9765.6)	19.7(31.2)	254.7(964.6)	147.5(349.3)	732.2(2431.9)	21.0(31.9)	453.6(2418.2)	287.1(1555.6)
Median	182.7	73.3	6.9	8.5	20.4	24.4	10.8	12.8	6.3
Range (min, max)	<0.7,>50000.0	7.1,>50000.0	<0.7,142.8	<0.7,5050.0	<0.7,1385.0	<0.7,11660.0	<0.7,181.4	<0.7,15130.0	<0.7,9480.0
Reference Interval(2.5th Percentile,97.5th Percentile)	<0.7,32606.0	7.7,37861.3	<0.7,129.4	<0.7,3434.9	<0.7,1216.3	<0.7,8335.2	<0.7,87.8	3.0,1559.2	<0.7,1362.7
N (%) with CA19-9≤25.0	21.7%	25.0%	77.5%	68.4%	60.0%	52.5%	80.0%	61.5%	83.8%
N (%) with CA19-9≤50.0	28.3%	42.5%	90.0%	81.6%	75.0%	62.5%	90.0%	76.9%	86.5%
N (%) with CA19-9≤75.0	34.2%	50.0%	95.0%	84.2%	82.5%	70.0%	95.0%	82.1%	86.5%

*Treatment-Naïve Exocrine Pancreatic; CRC - Colorectal;

It is recommended that each laboratory establish its own range, which may be unique to the population it serves depending upon geographical, patient, and environmental factors.

O. INSTRUMENT NAME

Lumipulse G1200 System (K142895)

P. PROPOSED LABELING

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

Q. CONCLUSION

The results of these analytical (nonclinical) and clinical studies demonstrate that the Lumipulse G CA19-9-N is substantially equivalent to the performance of the ARCHITECT® CA 19-9™ xR (K052000).

Regulation Number and Section

§ 866.6010 Tumor-associated antigen immunological test system.

(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.