Lumipulse G CA15-3 is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of CA 15-3 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMPULSE G System.

The assay is to be used as an aid in the management of patients previously diagnosed with stage II and III breast cancer. Serial testing for patient CA15-3 assay values should be used in conjunction with other clinical methods used for monitoring breast cancer.

WARNING: The concentration of CA 15-3 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 15-3 used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used of CA 15-3 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 CA 15-3 should not be used for cancer screening or diagnosis.

Device Description

Lumipulse G CA15-3 is an assay system, including a set of immunoassay reagents, for the quantitative measurement of CA 15-3 in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System.

Lumipulse G CA15-3 Immunoreaction Cartridges: REF 235102 The Lumipulse G CA15-3 Immunoreaction Cartridges 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-CA 15-3 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.

2.) Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.2 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-CA 15-3 monoclonal antibody (mouse), protein stabilizers (bovine and calf) and chemical stabilizers in 0.1 M sodium chloride/MES buffer. Preservative: sodium azide.

AI/ML Overview

Here's an analysis of the acceptance criteria and study detailed in the provided document, restructured to answer your specific questions:

1. A table of acceptance criteria and the reported device performance

The document primarily focuses on validating the Lumipulse G CA15-3 assay as "substantially equivalent" to a predicate device (ARCHITECT CA 15-3) and demonstrating its analytical and clinical performance. The acceptance criteria are largely implicit, based on meeting established guidelines (CLSI) and demonstrating satisfactory performance within defined ranges or against a predicate.

Acceptance Criteria Category	Specific Criteria/Target	Reported Device Performance (Lumipulse G CA15-3)
Precision/Reproducibility	Total precision (CV) ≤ 10% for controls and panels	20-day Precision: ≤ 3.3% (Range: 2.4% to 3.3%)
	Lot-to-Lot Total Precision (CV) ≤ 10%	≤ 3.3% (Range: 2.2% to 3.7%)
	Between-Lot Precision (CV)	≤ 4.8%
	Site-to-Site Total Precision (CV) ≤ 10%	≤ 6.7% (Range: 2.9% to 6.7%)
	Between-Site Precision (CV)	≤ 4.9%
Linearity/Reportable Range	Linear range established	1.7 U/mL to 434.8 U/mL
	High dose effect	No high dose effect observed up to 9,000 U/mL
Detection Limit	LoB, LoD, LoQ established	LoB: 0.022 U/mL, LoD: 0.053 U/mL, LoQ: 0.138 U/mL
	LoQ standard deviation ≤ 15% of mean	Yes, met for LoQ of 0.138 U/mL
Interfering Substances	Average interference ≤ ±10%	Demonstrated ≤ ±10% interference for all tested endogenous and therapeutic compounds
Method Comparison (vs. Predicate)	Correlation coefficient (r) with predicate	0.8537
	Slope (95% CI) with a predicate that includes 1	1.0512 (0.9674 to 1.1350)
	Intercept (95% CI) with a predicate that includes 0	0.4628 (-0.3189 to 1.2445)
Matrix Comparison	Slope for each tube type (vs. control) 95% CI between 0.9 and 1.1	Met for all tested tube types (SST, K2EDTA, Lithium Heparin, Sodium Heparin)
	Correlation coefficients (r) ≥ 0.9	Met for all tested tube types
Clinical Performance (Disease Monitoring)	Demonstrate ability to aid in monitoring disease status	Serial testing for CA15-3 assay values should be used in conjunction with other clinical methods. A ≥21% change indicates an approximate 25% likelihood of progression. A <21% change indicates an approximate 4% likelihood of progression.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

Precision (ARUP 20-day): n=80 for each of 6 panels.
Precision (Lot-to-Lot Reproducibility): n=90 for each of 6 samples (combined for Lots A, B, and C).
Precision (Site-to-Site Reproducibility): n=102 for each of 6 panels (for Lot A).
Linearity: Patient serum samples containing naturally expressed CA15-3. (Specific number not provided, but implies multiple dilutions for a range of samples).
Detection Limit: Not explicitly detailed on sample size but derived from technical measurements.
Interfering Substances: Human serum specimen pools with CA 15-3 concentrations ranging from approximately 30-35 U/mL, 80-100 U/mL, and 300-350 U/mL. (Number of pools or individual samples not provided, but implies multiple concentrations for each interferent).
Method Comparison: n=117 samples.
Matrix Comparison: Not explicitly detailed sample size, but involved various tube types (SST, K2EDTA, Lithium Heparin, and Sodium Heparin) versus control samples (Red top serum).
Monitoring of Disease State in Patients Diagnosed with Breast Cancer:
- Patients: 112 patients previously diagnosed with stage II and III breast cancer.
- Observations: 566 pairs of observations, with an average of 6.1 observations per patient.
- Data Provenance: Not explicitly stated as retrospective or prospective, nor country of origin, but described as patients "previously diagnosed with stage II and III breast cancer" and "monitoring recurrence or progressive disease," suggesting real-world patient data likely collected over time.
Expected values/Reference range (Apparently Healthy): N=356 (120 males, 236 females).
Expected values/Reference range (Apparently Healthy and Benign Subjects): N=591 (Includes the 356 healthy, plus additional benign groups: Benign Breast N=75, Benign Ovarian N=40, Urogenital N=40, Pregnant N=40, Hypertension N=40).
Expected values/Reference range (Subjects with Cancer): N=368 (Treatment Naïve Breast N=130, Uterine/Endometrial N=40, Ovarian N=40, Lung N=40, Colorectal N=38, Pancreatic N=40, Liver N=40).

The provenance details (country, retrospective/prospective) are not explicitly mentioned for most studies, although the patient cohorts for disease monitoring and reference ranges imply real clinical data collection.

3. 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)

This device is an in vitro diagnostic (IVD) assay for a biomarker (CA15-3).

For the analytical performance studies (precision, linearity, detection limits, interference, cross-reactivity), the "ground truth" is established through highly controlled laboratory procedures, reference materials, and defined statistical methods (e.g., CLSI guidelines). There is no "expert" per se establishing ground truth in the way a radiologist does for an imaging study. The accuracy is relative to reference measurements or established methods.
For the method comparison study (against ARCHITECT CA 15-3), the predicate device serves as the comparative reference, which itself would have been validated.
For the clinical performance study (Monitoring of Disease State), the ground truth for "disease progression" or "no progression" was not established by expert consensus of imaging or pathology specific to this study. Instead, disease status changes were assessed by "other clinical methods used for monitoring breast cancer" which likely includes physician assessment, imaging, and possibly pathology reports. The study assessed changes in CA15-3 levels against these "changes in disease status," which is the outcome used as the ground truth. No specific number or qualification of experts defining the clinical ground truth within this study is provided. However, the initial "staging of the patients was done according to AJCC 7th edition," which implies expert clinical assessment in their initial diagnosis.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

For an IVD assay measuring a biomarker, adjudication methods like 2+1 or 3+1 (common in image-based AI studies where human readers interpret images) are generally not applicable. The "ground truth" for quantitative assays is based on a reference standard or, in clinical studies, the established clinical diagnosis/status.

In the clinical monitoring study, the "change in disease status" serves as the clinical outcome (ground truth), but the method for determining this status retrospectively or prospectively, and if it involved adjudication, is not described.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This is an in vitro diagnostic (IVD) assay for a blood biomarker (CA15-3), not an AI-assisted diagnostic imaging device meant to assist human readers. Therefore, the concept of human readers improving with AI assistance is not applicable here.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, the analytical and clinical performance studies are standalone performance evaluations of the Lumipulse G CA15-3 assay. The device provides a quantitative measurement of CA15-3 in a sample. The performance characteristics (precision, linearity, detection limit, interference, method comparison) and the clinical utility for monitoring disease progression are all evaluated based on the assay's output directly, without a human in the loop interpreting the assay's numerical result in a subjective way. The clinical monitoring study, for instance, directly correlates changes in the assay's output with disease progression, demonstrating its standalone utility for this purpose.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

Analytical Studies: For analytical performance characteristics (precision, linearity, detection limit, interference, cross-reactivity), the ground truth is established by carefully prepared reference materials, spiked samples, and highly controlled laboratory procedures consistent with CLSI guidelines, aiming for accurate measurement against these known values.
Method Comparison: The ground truth is the measurement obtained by the legally marketed predicate device (ARCHITECT CA 15-3).
Clinical Monitoring Study: The ground truth for disease progression/no progression was based on outcomes data defined as "changes in disease status" over time, using "other clinical methods used for monitoring breast cancer." This likely refers to a combination of clinical assessments, imaging, and possibly pathology results, but no specific details on the exact methods or their adjudication are provided within the document.

8. The sample size for the training set

The terms "training set" and "test set" are typically used for machine learning or AI models. This document describes the validation of an IVD assay, not an AI system. Therefore, there isn't a traditional "training set" in the machine learning sense. The bulk of the studies (analytical and clinical performance) serve as the validation/testing to demonstrate the device's performance characteristics. If we loosely interpret "training set" as data used during the development phase to optimize the assay before formal validation, this information is not provided in the 510(k) summary, as it focuses on the performance of the finalized device.

9. How the ground truth for the training set was established

As explained above, there isn't a "training set" in the context of an AI model for this IVD device. The assay development would involve rigorous chemical and biological optimization, and calibration against reference materials, but this specific "ground truth establishment" for a training set is not applicable or detailed here.

Summary

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September 4, 2020

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

Re: K192524

Trade/Device Name: Lumipulse G CA15-3 Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: MOI Dated: August 5, 2020 Received: August 6, 2020

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 requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part

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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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

For comprehensive regulatory information about 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,

Ying (Katelin) Mao, Ph.D. Acting 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) K192524

Device Name LumipulseG CA15-3

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 Subpart C)
---------------	----------------------------------------------	---------------	---------------------------------------------

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Section 5

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510(k) SUMMARY

Lumipulse® G CA15-3

A. General Information

Submission Date: 12 Sep 2019

510(k) Number:

Submitter Information:

Fujirebio Diagnostics, Inc. Submitter: 201 Great Valley Parkway Malvern, PA 19355
Kristin Maddaloni Contact Person: Specialist, Requlatory Affairs Phone: (610) 395-2126 Fax: (610) 240-3803 Email: maddalonik@fdi.com

B. Purpose of Submission:

New device

C. Measurand:

Cancer antigen 15-3

D. Type of Test:

Quantitative assay, automated chemiluminescent enzyme immunoassay (CLEIA)

Applicant: نت

Fujirebio Diagnostics, Inc.

F. Proprietary and Established Names:

Lumipulse G CA15-3

G. Regulatory Information:

Regulation section: 1. 21 CFR § 866.6010
1. Classification: Class II
1. Product codes: MOI - system, test, immunological, antigen, tumor

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1. Panel: 82, Immunology

H. Intended Use:

1. Intended Use: Lumipulse G CA15-3 Immunoreaction Cartridges
  Lumipulse G CA15-3 is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of CA15-3 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System.

WARNING: The concentration of CA 15-3 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 15-3 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 15-3 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 CA15-3 should not be used for cancer screening or diagnosis.

1. Indications for use: Same as Intended Use.
1. Special conditions for use statement(s): Prescription use only.
1. Special instrument requirements: LUMIPULSE G1200 System

. Device Description:

Lumipulse G CA15-3 Immunoreaction Cartridges: | REF 235102 The Lumipulse G CA15-3 Immunoreaction Cartridges 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-CA 15-3 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine and mouse) and

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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.

2.) Enzyme-Labeled Antibody Solution

(Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.2 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-CA 15-3 monoclonal antibody (mouse), protein stabilizers (bovine and calf) and chemical stabilizers in 0.1 M sodium chloride/MES buffer. Preservative: sodium azide.

J. Substantial Equivalence:

1. Predicate device name(s): ARCHITECT CA 15-3
1. Predicate 510(k) number(s): K042732
1. Comparison with predicate:

Comparison between the Lumipulse® G CA15-3 and ARCHITECT CA15-3

Similarities and Differences
	Lumipulse® GCA15-3 (Proposed Device)	ARCHITECT CA15-3(Predicate Device)K042732
Device Type	In vitro diagnostic	Same
Classification	Class II	Same
Product Code	MOI	Same
Analyte	Cancer Antigen 15-3	Same
Regulation Number	21CFR § 866.6010	Same
Product Usage	Clinical and Hospital laboratories	Same
Principle of Operation	Automated QuantitativeChemiluminscent EnzymeImmunoassay (CLEIA)	Chemiluminscent MicroparticleImmunoassay (CMEIA)
Specimen CollectionMethod	Routine Phlebotomy Techniques	Same
Intended Use	Lumipulse G CA15-3 is aChemiluminescent EnzymeImmunoassay (CLEIA) for thequantitative determination of CA 15-3 in human serum or plasma(sodium heparin, lithium heparin, ordipotassium EDTA) on theLUMIPULSE G System.The assay is to be used as an aid inthe management of patientspreviously diagnosed with stage IIand III breast cancer. Serial testingfor patient CA15-3 assay values	The ARCHITECT CA 15-3 assayis a chemiluminescentmicroparticleimmunoassay (CMIA) for thequantitative determination of DF3defined antigen in human serumand plasma on the ARCHITECTiSystem. The ARCHITECT CA 15-3 assay is to be used as an aid inthe management of Stage II and IIIbreast cancer patients. Serialtesting for patient CA 15-3 assayvalues should be used inconjunction with other clinical

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Similarities and Differences
	Lumipulse® GCA15-3 (Proposed Device)	ARCHITECT CA15-3(Predicate Device)K042732
	should be used in conjunction withother clinical methods used formonitoring breast cancer.	methods for monitoring breastcancer
Instrument System	LUMIPULSE G System	ARCHITECT iSystem
Assay Type	Two-step sandwichimmunoassay based onchemiluminescenttechnology	Two-stepimmunoassay based onCMIAtechnology
Type of Specimen	Human serum and plasma (sodiumheparin, lithium heparin, ordipotassium EDTA)	Human serum and plasma(sodium heparin, lithium heparin,or tripotassium EDTA)
Assay Range	1.7 U/mL - 400 U/mL	0.5 U/mL - 800 U/mL

K. Standard/Guidance Document Referenced (if applicable):

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 EP09c - 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
CLSI EP34 - Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking; Approved Guideline - First Edition
. CLSI EP37 - Supplemental Tables for Interference Testing in Clinical Chemistry; Approved Guideline - First Edition

Test Principle: نــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

CA 15-3 in specimens specifically binds to anti-CA 15-3 monoclonal antibody (mouse) on the particles, and antigen-antibody immunocomplexes are formed. The particles are then washed and rinsed to remove unbound materials. Alkaline phosphatase (ALP; calf)-labeled anti-CA 15-3 monoclonal antibody (mouse) specifically binds to CA 15-3 of the immunocomplexes on the particles and additional immunocomplexes are formed. The particles are washed and rinsed to

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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 conjuqated to particles. Luminescence (at a maximum wavelength of 477 nm) is generated by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of CA 15-3.

Performance Characteristics M.

Data were generated using the LUMIPULSE G1200 System.

1. Analytical performance:
- a. Precision/Reproducibility:

The results of the 20-day precision calculations for Lumipulse G CA15-3 performed at Associated Regional and University Pathologists (ARUP) are shown below:

. Lot A ICs/Lot A Calibrators for Panels 1-6
The analyses determined the total precision for the Lumipulse G CA15-3 assay to be ≤ 3.3%. The total precision of the Lumipulse G CA15-3 for the six (6) panels ranged from 2.4% to 3.3%. The precision of all controls and panels for the 20-day Precision Study met the acceptance criteria of a CV ≤ 10%.

		Within-Run(Repeatability)		Between Run		Between-Day	Within-Laboratory(Total)
Sample	Mean(U/mL)	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	2.5	0.1	2.7%	0.0	0.0%	0.0	2.0%	0.1	3.3%
Panel 2	21.0	0.4	2.0%	0.3	1.6%	0.4	1.7%	0.6	3.1%
Panel 3	35.9	0.7	2.0%	0.3	0.9%	0.4	1.2%	0.9	2.5%
Panel 4	101.8	1.8	1.8%	1.2	1.2%	1.1	1.1%	2.4	2.4%
Panel 5	232.7	4.2	1.8%	4.2	1.8%	0.9	0.4%	6.0	2.6%
Panel 6	369.3	7.2	1.9%	6.0	1.6%	2.5	0.7%	9.7	2.6%

Summary for ARUP 20-day Precision (n=80 for each panel)

Lot-To-Lot Reproducibility for Combined Data

The precision analyses for the combined lot-to-lot analysis for Lots A, B and C determined the total precision for Lumipulse G PCT to be ≤ 3.7% in this study. The total precision for Lumipulse G CA15-3 to be ≤ 3.3% for the six (6) panels. The total precision of Lumipulse G CA15-3 ranged from 2.2% to 3.7%. The between-lot precision for Lumipulse G CA15-3 was ≤ 4.8%.

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The precision of controls and panels for the lot-to-lot reproducibility met the targeted acceptance criteria of a CV ≤ 10%.

	Mean(U/mL)	Between-Lot		Between Day		Between Run		Within-Run(Repeatability)		Within-Laboratory(Total)
Sample		SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	2.5	0.1	4.8%	0.0	0.3%	0.1	2.2%	0.1	2.5%	0.1	5.8%
Panel 2	20.0	0.6	3.2%	0.2	1.1%	0.2	1.0%	0.4	1.9%	0.8	4.0%
Panel 3	34.2	1.1	3.2%	0.4	1.1%	0.3	0.9%	0.5	1.6%	1.3	3.9%
Panel 4	96.7	2.9	3.0%	0.3	0.3%	0.6	0.6%	1.7	1.8%	3.5	3.6%
Panel 5	224.4	4.4	1.9%	0.0	0.0%	3.4	1.5%	4.6	2.0%	7.2	3.2%
Panel 6	360.1	6.9	1.9%	0.0	0.0%	5.7	1.6%	6.1	1.7%	10.8	3.0%

Summary of the Lot-to-Lot Reproducibility for the Combined Data for Lots A, B and C (n=90 for each sample)

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Site to Site Reproducibility for Combined Data

The precision analyses for the combined site-to-site analysis determined the total precision for Lumipulse G CA15-3 to be ≤ 6.7% for the 6 panels in this study. The total precision of Lumipulse G CA15-3 in the study ranged from 2.9% to 6.7%. The betweensite precision for Lumipulse G CA15-3 was ≤ 4.9%.

The precision of the controls and panels for the site-to-site reproducibility met the targeted acceptance criteria of a CV ≤10%.

			Between Site		Between Day	Between Run		Within-Run (Repeatability)		Reproducibility (Total)
Sample	Mean (U/mL)	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	2.4	0.1	4.9%	0.0	0.0%	0.1	4.1%	0.1	2.2%	0.2	6.7%
Panel 2	19.9	0.4	2.0%	0.2	1.1%	0.5	2.7%	0.3	1.7%	0.8	3.9%
Panel 3	33.7	0.6	1.8%	0.0	0.0%	1.0	2.8%	0.5	1.5%	1.3	3.7%
Panel 4	96.0	0.9	1.0%	1.0	1.1%	1.8	1.8%	1.7	1.7%	2.8	2.9%
Panel 5	219.2	4.2	1.9%	3.2	1.4%	4.4	2.0%	4.2	1.9%	8.0	3.7%
Panel 6	348.1	3.1	0.9%	7.0	2.0%	6.8	2.0%	5.1	1.5%	11.5	3.3%

Summary of the Site-to-Site Reproducibility for the Combined Data for Lot A (n=102 for each panel)

b. Linearity/assay reportable range:

Lumipulse G CA15-3 the LUMIPULSE G1200 System demonstrated linearity in a study consistent with the guidelines in the CLSI Guideline EP6-A. High pools were created using patient serum samples that contained naturally expressed CA15-3 and diluted with a low patient serum sample pool. The linearity was found in the range of 1.7 U/mL to 434.8 U/mL. Lumipulse G CA15-3 correlated with expected concentrations according to the linear regression formula:

Range(U/mL)	Slope(95% CI)	Intercept(95% CI)	R2
1.7-400	0.965(0.956, 0.974)	-0.226(-0.316, -0.136)	0.9985

High dose effect is a phenomenon whereby very high level specimens may read within the dynamic range of the assay. For Lumipulse G CA15-3 on the LUMIPULSE G1200 System, no high dose effect was observed for samples containing approximately 9,000 U/mL of CA 15-3.

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Image /page/10/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized, abstract symbol on the left, composed of blue and white shapes. To the right of the symbol, the text "FUJIREBIO" is displayed in a bold, blue sans-serif font, with a registered trademark symbol next to it. Below "FUJIREBIO", the words "Diagnostics, Inc." are written in a smaller, black sans-serif font.

c. Traceability, Stability, Expected values (controls, calibrators, or methods):
Calibration of the Lumipulse G CA15-3 is traceable to in-house reference calibrators, whose values have been assigned to correlate to Fujirebio Diaqnostics' CA 15-3 Radioimmunoassay.

Shelf life

The shelf life for Lumipulse G CA15-3 Immunoreaction Cartridges and the Lumipulse G CA15-3 Calibrators is 12 months at 2-10°C.

On board the LUMIPULSE G1200

The Lumipulse G CA15-3 Immunoreaction Cartridges are sealed and stored at 4-12°C. To reduce risk for any misuse, the package insert states The Lumipulse G CA15-3 Cartridges can be stored 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 CA15-3 Immunoreaction Cartridges and the Lumipulse G CA15-3 Calibrators are shipped at 2-10°C.

d. Detection limit:

The Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) of Lumipulse G CA15-3 on the LUMIPULSE G1200 System is ≤0.138 U/mL.

1)LoB and LoD

The LoB for Lumipulse G CA15-3 was 0.022 U/mL. The LoD for Lumipulse G CA15-3 on the LUMIPULSE G1200 System was 0.053 U/mL, determined consistent with the guidelines in the CLSI Guideline EP17-A2.

2)Limit of Quantitation (LoQ)

The LoQ for Lumipulse G CA15-3 on the LUMIPULSE G1200 System was determined to be 0.138 U/mL, when analyzed in accordance to the guidelines in the CLSI EP17-A2. The LoQ is defined as the concentration of CA 15-3 at which the standard deviation is no more than 15% of the mean.

e. Interfering Substances

Lumipulse G CA15-3 on the LUMIPULSE G1200 System demonstrated an average interference of ±10% for each compound shown in the table below, in a study consistent with the quidelines in the CLSI EP07 and EP37. Human serum specimen pools with CA 15-3 concentrations ranging from approximately 30-35 U/mL, 80-100 U/mL, and 300-350 U/mL were supplemented with potentially interfering compounds. The following compounds were tested using Lumipulse G CA15-3 and found not to interfere with the assay.

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Image /page/11/Picture/1 description: The image contains the logo for "FUJIREBIO Diagnostics, Inc." The logo consists of a blue abstract shape on the left, resembling a stylized water droplet or a leaf. To the right of the shape, the word "FUJIREBIO" is written in a bold, blue sans-serif font. Below "FUJIREBIO", the words "Diagnostics, Inc." are written in a smaller, less bold, sans-serif font, also in blue.

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
	1,000 mg/dL
Total Protein (Human SerumAlbumin)	12 g/dL
	15 g/dL
	5 g/dL
Immunoglobulin G (IgG)	19.7 mg/dL
Biotin
Human Anti-Mouse Antibodies(HAMA IgG)	1,000 ng/mL
Rheumatoid Factor (RF) IgM	1,000 IU/mL

TherapeuticInterferences	Drug	Test Concentration
Abemaciclib		24 mg/dL
Acetaminophen		20 mg/dL
Acetylsalicylic Acid		100 mg/dL
Acetylcysteine		166 mg/dL
Albumin-bound paclitaxel		27 mg/dL
Alpelisib		18 mg/dL
Ampicillin-Na		100 mg/dL
Ascorbic Acid		30 mg/dL
Atezolizumab		72 mg/dL
ß-Estradiol		0.67 mg/dL
Capecitabine		128 mg/dL
Carboplatin		100 mg/dL
Cefoxitin		660 mg/dL
Cisplatin		17.5 mg/dL
Cyclophosphamide		80.0 mg/dL
Cyclosporine		0.5 mg/dL
Diethylstilbestrol		2.5 mg/dL
Docetaxel		10 mg/dL
Doxorubicin HCI		5.0 mg/dL
Doxycycline		3 mg/dL
Epirubicin	12 mg/dL
Eribulin	0.14 mg/dL
Etoposide	1.0 mg/dL
Everolimus	1.2 mg/dL
Exemestane	12 mg/dL
5-Fluorouracil	28.0 mg/dL
Flutamide	1.0 mg/dL
Fulvestrant	51 mg/dL
Gemcitabine	128 mg/dL
Heparin	5000 U/L
Ibuprofen	50 mg/dL
Lapatinib	90 mg/dL
Levodopa	2 mg/dL
Liposomal doxorubicin	5 mg/dL
Megestrol acetate	3.96 mg/dL
Methotrexate	45.0 mg/dL
Methyldopa	2.25 mg/dL
Metronidazole	12.3 mg/dL
Mitomycin	7.5 mg/dL
Olaparib	18 mg/dL
Paclitaxel	0.35 mg/dL
Palbociclib	8 mg/dL
Pertuzumab	50 mg/dL
Phenylbutazone	40 mg/dL
Ribociclib	36 mg/dL
Rifampicin	6 mg/dL
Talazoparib	0.06 mg/dL
Tamoxifen	6.0 mg/dL
Testosterone	3.3 mg/dL
Theophylline	10 mg/dL
Vinblastine sulfate	0.13 mg/dL
Vincristine	0.15 mg/dL
Vinorelbine	3 mg/dL
Herceptin®	40.0 mg/dL

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Image /page/12/Picture/1 description: The image is a logo for Fujirebio Diagnostics, Inc. The logo features a stylized blue and green graphic on the left, resembling a water droplet and vertical lines. To the right of the graphic is the company name, "FUJIREBIO" in large, bold, blue letters, with "Diagnostics, Inc." in a smaller font size underneath.

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Image /page/13/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 white shapes. To the right of the graphic, the word "FUJIREBIO" is written in large, bold, blue letters. Below "FUJIREBIO", the words "Diagnostics, Inc." are written in a smaller, black font.

f. Cross Reactivity

Interferent	Test Concentration	Highest Observed % Cross Reactivity
CA19-9	11,000 U/mL	0.003
CA125	11,000 U/mL	0.024
AFP	500 ng/mL	-0.063
CEA	5,000 ng/mL	8.246

g. Assay cut-off: See Clinical Cutoff in 4 below.

2. Comparison studies:

a. Method Comparison

System in a study consistent with the guidelines in CLSI EP09-A3.

Lumipulse G CA15-3 method comparison was performed on the LUMIPULSE G1200 System in a study consistent with the quidelines in CLSI EP09-A3. The weighted Deming regression method was used to compare the performance of Lumipulse G CA15-3 to the ARCHITECT CA 15-3. The samples tested ranged from 5.3 to 375.6 U/mL for Lumipulse G CA15-3 and 5.1 to 1004.4 U/mL for ARCHITECT CA 15-3. The data are summarized in the following table.

Lumipulse G CA15-3 vs. ARCHITECT CA 15-3
n	CorrelationCoefficient (r)	Intercept(95% CI)	Slope(95% CI)	Mean Difference(U/mL)
117	0.8537	0.4628(-0.3189 to 1.2445)	1.0512(0.9674 to 1.1350)	-3.427

b. Matrix Comparison

The Lumipulse G CA15-3 matrix comparison study was performed to evaluate the difference across tube types (SST. K2EDTA, Lithium Heparin, and Sodium Heparin) versus the means of the control samples (Red top serum) analyzed per CLSI guideline EP09c. The slope for each tube type when compared to the control had 95% confidence intervals that lay entirely within the range 0.9 to 1.1 and the correlation coefficients were ≥ 0.9.

3. Clinical studies:

a. Clinical sensitivity:
Not applicable
b. Clinical specificity:
Not applicable
c. Other clinical supportive data

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Image /page/14/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 that resemble a water droplet. To the right of the graphic, the text "FUJIREBIO" is displayed in a bold, blue font, with the words "Diagnostics, Inc." appearing in a smaller font size below.

Monitoring of Disease State in Patients Diagnosed with Breast Cancer

The effectiveness of Lumipulse G CA15-3 as an aid in monitoring recurrence or progressive disease in patients with breast cancer who have detectable levels of CA15-3 at some point in their disease process was determined by assessing changes in CA15-3 levels in serial serum samples from 112 patients compared to changes in disease status. The staging of the patients was done according to AJCC 7th edition. A study involving a total of 566 pairs of observations was undertaken with an average number of 6.1 observations per patient. A positive change in CA15-3 was defined as an increase in the value that was at least 21% greater than the previous value of the test. This level of change takes into account the biological and analytical variability of the assay. Twenty-five percent (25%) or 14/57 of the patient samples with a positive change correlated with the disease progression, indicating a change in CA15-3 value of <21% is associated with decreased likelihood of progression.

PerformanceMeasurement	Value	SE	Lower Cl	Upper Cl
Sensitivity	51.85 (14/27)	15.71	20.5	83.2
Specificity	86.77 (282/325)	2.02	82.73	90.8
PPV	24.56 (14/57)	7.38	9.85	39.28
NPV	95.59 (282/295)	1.97	91.67	99.52
1-NPV	4.41%	1.97	8.33	0.48
PLR	3.92	0.33	2.03	7.57
NLR	0.55	0.34	0.28	1.08
Prevalence (%)	7.7% (27/352)

Lumipulse G CA15-3 Primary Progression Performance Measurements

Change in Disease Status Per Sequential Pair In Stages II and III Patients

Change inConcentration	CA15-3Progression	No Progression	Total
Suspect ≥21%	14	43	57
No <21%	13	282	295
Total	27	325	352

Lumipulse G CA15-3 Full Progression Performance Measurements

PerformanceMeasurement	Value	SE	Lower Cl	Upper Cl
Sensitivity	48.89 (22/45)	10.75	27.59	70.19
Specificity	88.29 (460/521)	1.47	85.38	91.2
PPV	26.51 (22/83)	6.16	14.31	38.7
NPV	95.24(460/483)	1.48	92.31	98.16
PLR	4.18	0.25	2.52	6.91
NLR	0.58	0.21	0.38	0.88

Change in Disease Status Per Sequential Pair for All Progression Events

Change in CA15-3Concentration	Progression	No Progression	Total
Suspect ≥21%	22	61	83
No <21%	23	460	483
Total	45	521	566

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Image /page/15/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized blue and green symbol on the left, followed by the company name in blue text. The word "FUJIREBIO" is in a larger, bolder font than "Diagnostics, Inc.", which is placed below it.

Lower prevalence of progression events was observed during the course of this study in all different stages of disease, demonstrating similar test performance throughout the testing. This can be primarily explained by significant improvement in breast cancer treatment.

Based on this information, an interpretation of results section will be added to the labeling to the table below.

Change in CA15-3 Value and Associated Interpretation

Change in CA15-3 Concentration	Interpretation
<21%	Likelihood of progression isapproximately 4%
≥21%	Likelihood of progression isapproximately 25%

Based on the results observed in this study, the likelihood of having progression when a positive result is present (change in CA15-3 value ≥21%) is approximately 25%, while the likelihood of progression when a change in CA15-3 value <21% is approximately 4%. However, the likelihood of having progression when a positive result is present (a change in CA15-3 value ≥21%) is only 25%, indicating that 75% of women with CA15-3 value change ≥21% do not have progression.

4. Clinical cut-off:

See Expected Values below.

1. Expected values/Reference range:
  Serum specimens obtained from apparently healthy males and females were tested using Lumipulse G CA15-3 per CLSI EP28-A3c.

The observed ranges are as follows:

	ApparentlyHealthy Males andFemales(Combined)	Apparently HealthyMales	Apparently HealthyFemales
N	356	120	236
Mean (SD)	16.3 (6.8)	16.2 (6.1)	16.4 (7.1)
Median	15.1	15.3	15.1
Range (min, max)	4.3, 41.4	4.3, 40.0	5.6, 41.4
Reference Interval (2.5thPercentile, 97.5th Percentile)	6.5, 32.5	6.2, 30.3	6.5, 33.9
N (%) with CA 15-3 ≤ 15.0	49.7%	50.0%	49.6%
N (%) with CA 15-3 ≤ 30.0	95.8%	96.7%	95.3%
N (%) with CA 15-3 ≤ 35.0	99.2%	99.2%	99.2%

All Lumipulse G CA15-3 concentrations are presented in U/mL.

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In addition to the normal cohot, serum speciment of the benign conditions and subjects with malignant diseases were tested using Lumipulse G CA15-3 per Clinical and Laboratory Standards Institute (CLSI) EP28-A3c. All Lumipulse G CA15-3 concentrations are presented in U/mL.

The observed ranges are as follows:

Reference Intervals per Group (Apparently Healthy and Benign Subjects)
	ApparentlyHealthy andBenign(All)	ApparentlyHealthy Malesand Females(Combined)	All	Apparently Healthy Females		ApparentlyHealthyMales	BenignBreast	BenignOvarian	Urogenital	Pregnant	Hypertension
N	591	356	236	90	119	120	75	40	40	40	40
Mean (SD)	17.0 (7.4)	16.3 (6.8)	16.4 (7.1)	14.6 (6.8)	16.9 (6.5)	16.2 (6.1)	18.4 (8.7)	16.1 (7.6)	20.1 (9.1)	16.0 (6.4)	18.6 (7.4)
Median	15.7	15.1	15.1	13.3	15.9	15.3	18.2	14.8	18.3	15.3	17.0
Range (min,max)	4.3, 55.2	4.3, 41.4	5.6, 41.4	5.6, 34.2	6.4, 34.2	4.3, 40.0	6.1, 55.2	6.0, 33.1	8.0, 39.5	6.3,28.9	7.4, 38.9
ReferenceInterval (2.5thPercentile, 97.5thPercentile)	6.6, 34.2	6.5, 32.5	6.5, 33.9	60, 33.5	7.2, 31.0	6.2, 30.3	6.6, 44.5	6.0, 33.1	8.0, 39.5	6.3, 28.9	7.4, 38.7
N (%) withCA15-3 ≤ 15.0	46.9%	49.7%	49.6%	63.3%	42.0%	50.0%	37.3%	52.5%	42.5%	50.0%	35.0%
N (%) withCA15-3 ≤ 30.0	94.8%	95.8%	95.3%	95.6%	97.5%	96.7%	93.3%	92.5%	87.5%	100.0%	92.5%
N (%) withCA15-3 ≤ 35.0	98.3%	99.2%	99.2%	100.0%	100.0%	99.2%	97.3%	100.0%	90.0%	100.0%	97.5%

Reference Intervals per Group (Apparently Healthy and Benign Subjects)

All Lumipulse G CA15-3 concentrations are presented in U/mL

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Reference Intervals per Group (Subjects with Cancer)
	Cancers(All)	TreatmentNaïveBreast (AllStages)	Uterine/Endometrial	Ovarian	Lung	Colorectal	Pancreatic	Liver
N	368	130	40	40	40	38	40	40
Mean (SD)	31.1 (52.4)	24.4 (31.0)	28.0 (32.9)	59.0(123.9)	44.6 (55.1)	22.5 (30.6)	28.0 (20.0)	25.3 (25.2)
Median	20.1	19.7	16.1	25.8	26.2	16.6	22.9	18.1
Range (min,max)	3.8, 749.0	3.8, 350.2	5.6, 190.0	6.0, 749.0	8.7, 283.1	4.5, 200.2	9.2, 124.7	8.3, 143.0
ReferenceInterval (2.5thPercentile,97.5thPercentile)	7.0, 136.7	6.9, 58.3	5.6, 187.6	6.0, 738.4	8.7, 280.0	6.5, 47.9	9.3, 123.4	8.3, 141.9
N (%) withCA15-3 ≤ 15.0	28.8%	29.2%	47.5%	15.0%	17.5%	42.1%	10.0%	40.0%
N (%) withCA15-3 ≤ 30.0	75.5%	80.0%	75.0%	60.0%	57.5%	89.5%	75.0%	82.5%
N (%) withCA15-3 ≤ 35.0	81.0%	86.2%	80.0%	65.0%	70.0%	94.7%	77.5%	82.5%

..............................................................................................................................................................................

All Lumipulse G CA15-3 concentrations are presented in U/mL

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

N. Proposed Labeling

The labeling satisfies the requirements of 21 CFR Part 809.10.

O. Conclusion

The results of these analytical) and clinical studies demonstrate that the Lumipulse G CA15-3 assay is substantially equivalent to the performance of the ARCHITECT CA 15-3 assay.

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.