Lumipulse® G Risk of Ovarian Malignancy Algorithm (ROMA®) is a qualitative serum and plasma (lithium heparin or dipotassium EDTA) test that combines the results of Lumipulse G CA 1251 and menopausal status into a numerical score.

Lumipulse G ROMA is intended to aid in assessing whether a premenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery. Lumipulse G ROMA is indicated for women who meet the following criteria: over age 18; ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist. Lumipulse G ROMA must be interpreted in conjunction with an independent clinical and radiological assessment. The test is not intended as a screening or stand-alone diagnostic assay.

PRECAUTION: Lumipulse G ROMA should not be used without an independent clinical /radiological evaluation and is not intended to be a screening test or to determine whether a patient should proceed to surgery. Incorrect use of Lumipulse G ROMA carries the risk of unnecessary testing, surgery, and/or delayed diagnosis.

Device Description

Lumipulse GROMA is a qualitative serum and plasma test that combines the results of 2 analytes, HE4 (Lumipulse G HE4) and CA125 (Lumipulse G CA 125 II) and menopausal status into a numerical score between 0.00 and 10.00. The premenopausal status must be based on ovarian function determined with information available from clinical evaluation and medical history.

The test system consists of Lumipulse G HE4, Lumipulse G CA 125 II, the Lumipulse G ROMA Calculator Tool and the LUMIPULSE G1200 System. The LUMIPULSE G1200 System is not capable of calculating the ROMA score. The immunoassays are performed according to the directions detailed in each product insert.

Both Lumipulse G HE4 and Lumipulse G CA 125 Il are previously 510(k) cleared Class II devices (K151378 and K142895 respectively). The Lumipulse G HE4 assay is a chemiluminescent enzyme immunoassay (CLEIA) for the quantitative determination of HE4 antigen in human serum and plasma (lithium heparin or dipotassium EDTA) on the LUMIPULSE G System. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer. Lumipulse G CA 125 II assay is a chemiluminescent enzyme immunoassay (CLEIA) for the quantitative determination of CA125 in human serum and plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMPULSE G System. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with ovarian cancer. Serial testing for patient CA125 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

Lumipulse G ROMA scores (numerical score from 0.00 -10.00) for both premenopausal and postmenopausal women are calculated using the Lumipulse G ROMA Calculator Tool to indicate a low likelihood or high likelihood for finding malignancy on surgery using the value of the 2 immunoassays (Lumipulse G HE4 and Lumipulse G CA125II).

AI/ML Overview

Here’s a summary of the acceptance criteria and the study proving the device meets them, based on the provided FDA 510(k) submission for Lumipulse G ROMA:

1. Table of Acceptance Criteria and Reported Device Performance

The submission does not explicitly state "acceptance criteria" in a quantitative manner for clinical performance in the way usually seen for AI/ML devices (e.g., minimum sensitivity or specificity targets). Instead, it demonstrates substantial equivalence to a predicate device and provides performance metrics (sensitivity, specificity, PPV, NPV) for direct disease detection and adjunctive use with Initial Cancer Risk Assessment (ICRA).

Given that the purpose of the submission is to demonstrate "substantial equivalence" to a predicate device, the implied acceptance criterion for clinical performance is that the Lumipulse G ROMA's performance should be comparable or non-inferior to the predicate device and demonstrate utility for its intended use. For analytical performance, the acceptance criteria are typically met by demonstrating acceptable precision, linearity, analytical specificity, and method comparison to the predicate. The clinical study results presented are the "reported device performance."

Category	Acceptance Criteria (Implied / Demonstrated)	Reported Device Performance (Lumipulse G ROMA)
Clinical Performance	Substantial Equivalence to Predicate (ROMA (HE4 EIA + ARCHITECT CA 125 II)) and Utility for Intended Use: To demonstrate aid in assessing high or low likelihood of malignancy in ovarian adnexal mass for pre/postmenopausal women, with acceptable sensitivity, specificity, PPV, and NPV.	For Stratification into High/Low Likelihood of Malignancy (EOC only):Premenopausal: Sensitivity 100.0% (9/9), Specificity 74.9% (167/223), PPV 13.8% (9/65), NPV 100.0% (167/167)Postmenopausal: Sensitivity 92.1% (35/38), Specificity 77.6% (111/143), PPV 52.2% (35/67), NPV 97.4% (111/114)Adjunctive Use with ICRA (All Malignancies & LMP):Combined Premenopausal & Postmenopausal: Sensitivity 88.1%, Specificity 67.5%, PPV 38.3%, NPV 96.1%(Statistically significant improvement in NPV from 93.1% (ICRA alone) to 96.1% (Adjunctive)).
Method Comparison	Strong correlation with the predicate device for both premenopausal and postmenopausal women.	Premenopausal Women (n=53): Correlation Coefficient (r) = 0.9977, Intercept (-0.004), Slope (1.005)Postmenopausal Women (n=115): Correlation Coefficient (r) = 0.9953, Intercept (-0.103), Slope (0.999)
Matrix Comparison	Equivalence between serum and K2 EDTA plasma samples.	Premenopausal (n=86): y= 1.001(x) - 0.072; r=0.9983Postmenopausal (n=86): y= 1.004(x) - 0.058; r=0.9988
Precision (Lot-to-Lot)	Acceptable %CV for ROMA scores across different lots.	Overall Total %CV for Premenopausal ROMA: 4.6% (Panel 1) to 0.0% (Panel 6)Overall Total %CV for Postmenopausal ROMA: 2.4% (Panel 1) to 0.1% (Panel 6)
Reproducibility (Site-to-Site)	Acceptable %CV for ROMA scores across different sites.	Overall Total %CV for Premenopausal ROMA: 8.1% (Panel 1) to 0.1% (Panel 6)Overall Total %CV for Postmenopausal ROMA: 5.2% (Panel 1) to 0.2% (Panel 6)
Analytical Specificity	Minimal interference from common endogenous interferents.	Mean Percent (%) Difference for all tested interferents (Free Bilirubin, Conjugated Bilirubin, Triglycerides, Hemoglobin, Total Protein, Immunoglobulin G, Biotin, HAMA, Rheumatoid Factor) was within a range of -2% to +1% for both pre- and post-menopausal ROMA scores.

2. Sample Sizes and Data Provenance for Test Set (Clinical Study)

Sample Size: A total of 450 women were evaluable in the clinical study test set.
- Premenopausal: 244
- Postmenopausal: 206
Data Provenance: The study was described as a prospective, multi-center, blinded clinical trial. The specific country of origin is not mentioned in the provided text.

3. Number of Experts and Qualifications for Ground Truth (Clinical Study)

Number of Experts: Not explicitly stated as a count of individual experts.
Qualifications: "An initial cancer risk assessment (ICRA) was completed by a non-gynecological oncologist". The specific years of experience or board certifications are not provided.
Ground Truth for Clinical Study: Histopathology reports collected after surgery were the definitive ground truth for malignancy.

4. Adjudication Method for the Test Set

The text describes the clinical trial as "blinded," implying that those interpreting the Lumipulse G ROMA results were blinded to the initial cancer risk assessment (ICRA) and histopathology, and vice-versa for the ICRA.
Adjudication Method: Not explicitly detailed beyond the "blinded" nature and the use of histopathology as the definitive truth. There is no mention of a 2+1 or 3+1 type of expert consensus for the initial clinical assessment.

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

The study evaluated the adjunctive use of Lumipulse G ROMA with Initial Cancer Risk Assessment (ICRA). This is a form of comparative effectiveness study involving human readers (non-gynecological oncologists) with and without the device.
Effect Size (Improvement with AI vs. without AI assistance):
- The study showed a statistically significant improvement in the Negative Predictive Value (NPV) when Lumipulse G ROMA was used adjunctively with ICRA.
- NPV for classifying benign patients into the low likelihood group increased from 93.1% (ICRA alone) to 96.1% (Adjunctive). This represents a 3% absolute increase in NPV.
- Other metrics for adjunctive use compared to ICRA alone:
  - Sensitivity increased from 72.6% to 88.1%
  - Specificity decreased from 84.2% to 67.5%
  - PPV decreased from 51.3% to 38.3%

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance was done. The sections titled "Use of Lumipulse G ROMA for stratification into low likelihood and high likelihood groups for finding malignancy on surgery" and "The performance of Lumipulse G ROMA for stratification into low likelihood and high likelihood groups for premenopausal and postmenopausal women with epithelial ovarian cancer (EOC) only" directly present the performance of the Lumipulse G ROMA algorithm in isolation.
The results are presented for premenopausal and postmenopausal women separately, and for all cancer and LMP tumors combined.

7. Type of Ground Truth Used

For the clinical study, the definitive ground truth was histopathology reports collected after surgery. This is considered a high-quality, objective ground truth.

8. Sample Size for the Training Set

The submission does not explicitly mention a separate training set for the Lumipulse G ROMA algorithm itself.
The ROMA algorithm's equation (Predictive Index for premenopausal and postmenopausal women) and clinical cut-offs (1.31 and 2.77) are identical to the predicate device (ROMA (HE4 EIA + ARCHITECT CA 125 II) K103358). This suggests that the algorithm itself was likely developed and validated previously, and this submission focuses on the performance of the Lumipulse G HE4 and Lumipulse G CA125II assays within the established ROMA framework. The provided study serves as a clinical validation for the proposed device using these specific assays.

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

Given that the algorithm and its cut-offs appear to be directly adopted from the predicate device and its previous development, the specific details of how the original training set for the ROMA algorithm's ground truth was established are not provided in this document.
For the assays themselves (Lumipulse G HE4 and CA125II), which are previously cleared devices, their calibration and standardization would have been established against reference materials, but this isn't a "training set" for the algorithm.

Summary

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

May 16, 2016

Fujirebio Diagnostics, Inc. Ms. Diana Dickson Director, Clinical and Regulatory Science 201 Great Valley Parkway Malvern PA 19355

Re: K160090

Trade/Device Name: Lumipulse® G ROMA® Regulation Number: 21 CFR 866.6050 Regulation Name: Ovarian adnexal mass assessment score test system Regulatory Class: II Product Code: ONX Dated: April 14, 2016 Received: April 15, 2016

Dear Ms. Dickson:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21. Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

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

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

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

Sincerely yours.

Kelly Oliner -S

For.

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

Enclosure

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Indications for Use

510(k) Number (if known) K160090

Device Name Lumipulse® G ROMA®

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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510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.

510(k) Number:

K160090

Purpose for Submission:

New device

Measurand:

ROMA (Risk of Ovarian Malignancy Algorithm) - Ovarian adnexal mass assessment score based on 2 analytes

Type of Test:

Software algorithm and 2 immunoassays

Applicant:

Address:	Fujirebio Diagnostics, Inc.201 Great Valley ParkwayMalvern, PA 19355
Contact person:	Diana Dickson(610) 240-3917dicksond@fdi.com

Summary preparation date: May 16, 2016

Proprietary and Established Names:

Lumipulse® G ROMA®

Regulatory Information:

Regulation section: 1. 21 CFR §866.6050 - Ovarian adnexal mass assessment score test system
1. Classification: Class II
1. Product code: ONX; Ovarian adnexal mass assessment score test system
1. Panel: 82, Immunology

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Intended Use:

1. Intended use(s): For In Vitro Diagnostic Use Only.
  Lumipulse® G Risk of Ovarian Malignancy Algorithm (ROMA®) is a qualitative serum and plasma (lithium heparin or dipotassium EDTA) test that combines the results of Lumipulse G HE4, Lumipulse G CA125II and menopausal status into a numerical score.

Lumipulse G ROMA is intended to aid in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery. Lumipulse G ROMA is indicated for women who meet the following criteria: over age 18; ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist. Lumipulse G ROMA must be interpreted in conjunction with an independent clinical and radiological assessment. The test is not intended as a screening or stand-alone diagnostic assay.

1. Indication(s) 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:

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conjunction with other clinical methods used for monitoring ovarian cancer. Lumipulse G CA 125 II assay is a chemiluminescent enzyme immunoassay (CLEIA) for the quantitative determination of CA125 in human serum and plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMPULSE G System. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with ovarian cancer. Serial testing for patient CA125 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

Substantial Equivalence Information:

1. Predicate device name(s): ROMA™ (HE4 EIA + ARCHITECT CA 125 II)
1. Predicate 510(k) number(s): K103358
1. Comparison with predicate:

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Similarities
	Lumipulse® G ROMA®(Proposed Device)	ROMA (HE4 EIA +ARCHITECT CA 125 II)(Predicate Device)K103358
Device Type	In vitro diagnostic	In vitro diagnostic
Classification	Class II	Class II
Regulation Number	21CFR § 866.6050Ovarian adnexal massassessment score testsystem	21CFR § 866.6050Ovarian adnexal massassessment score testsystem
Product Usage	Clinical and Hospitallaboratories	Clinical and Hospitallaboratories
Intended Use	Lumipulse G Risk of OvarianMalignancy Algorithm(ROMA) is a qualitativeserum and plasma (lithiumheparin or dipotassiumEDTA) test that combines theresults of Lumipulse G HE4,Lumipulse G CA 125 II™ andmenopausal status into anumerical score.Lumipulse G ROMA isintended to aid in assessingwhether a premenopausal orpostmenopausal woman whopresents with an ovarianadnexal mass is at high orlow likelihood of findingmalignancy on surgery.Lumipulse G ROMA isindicated for women whomeet the following criteria:over age 18; ovarian adnexalmass present for whichsurgery is planned, and notyet referred to an oncologist.Lumipulse G ROMA must beinterpreted in conjunction withan independent clinical andradiological assessment.The test is not intended as ascreening or stand-alonediagnostic assay.	The Risk of OvarianMalignancy Algorithm(ROMA) is a qualitative serumtest that combines the resultsof HE4 EIA, ARCHITECT CA125 II™ and menopausalstatus into a numerical score.ROMA is intended to aid inassessing whether apremenopausal orpostmenopausal woman whopresents with an ovarianadnexal mass is at high orlow likelihood of findingmalignancy on surgery.ROMA is indicated for womenwho meet the followingcriteria: over age 18; ovarianadnexal mass present forwhich surgery is planned, andnot yet referred to anoncologist. ROMA must beinterpreted in conjunction withan independent clinical andradiological assessment. Thetest is not intended as ascreening or stand-alonediagnostic assay.
	Similarities
	Lumipulse® G ROMA®(Proposed Device)	ROMA (HE4 EIA +ARCHITECT CA 125 II)(Predicate Device)K103358
Black box warning(PRECAUTION)	Should not be used withoutan independent clinical/radiological evaluation and isnot intended to be ascreening test or to determinewhether a patient shouldproceed to surgery. Incorrectuse carries the risk ofunnecessary testing, surgery,and/or delayed diagnosis	Should not be used withoutan independent clinical/radiological evaluation and isnot intended to be ascreening test or to determinewhether a patient shouldproceed to surgery. Incorrectuse carries the risk ofunnecessary testing, surgery,and/or delayed diagnosis
Specimen Collection Method	Routine PhlebotomyTechniques	Routine PhlebotomyTechniques
Serum Analyte	HE4 and CA125	HE4 and CA125
Device Type	Algorithm(Qualitative, numeric)	Algorithm(Qualitative, numeric)
Equation used for test	Premenopausal woman:Predictive Index (PI) = -12.0 +$2.38LN[HE4] +0.0626LN[CA 125]$Postmenopausal woman:Predictive Index (PI) = -8.09 +$1.04LN[HE4] + 0.732LN[CA125]$$ROMA = exp(PI) / [1 +exp(PI)] *10$	Premenopausal woman:Predictive Index (PI) = - 12.0 +$2.38LN[HE4] +0.0626LN[CA 125]$Postmenopausal woman:Predictive Index (PI) = -8.09 +$1.04LN[HE4] + 0.732LN[CA125]$$ROMA = exp(PI) / [1 +exp(PI)] *10$
Clinical Cut-off	Premenopausal:Lumipulse G ROMA score ≥1.31 = High likelihood offinding malignancyLumipulse G ROMA score <1.31 = Low likelihood offinding malignancyPostmenopausal:Lumipulse G ROMA score ≥2.77 = High likelihood offinding malignancyLumipulse G ROMA score <2.77 = Low likelihood offinding malignancy	Premenopausal:ROMA score ≥ 1.31 = Highlikelihood of findingmalignancyROMA score < 1.31= Lowlikelihood of findingmalignancyPostmenopausal:ROMA score ≥ 2.77 = Highlikelihood of findingmalignancyROMA score < 2.77 = Lowlikelihood of findingmalignancy
Similarities
	Lumipulse® G ROMA®(Proposed Device)	ROMA (HE4 EIA +ARCHITECT CA 125 II)(Predicate Device)K103358
Software	Provided as separate CD-ROM for manual entry ofassay values using softwareon a Personal Computer (PC)to produce the ROMA result	Provided as separate CD-ROM for manual entry ofassay values using softwareon a Personal Computer (PC)to produce the ROMA result

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Differences
	Lumipulse® G ROMA®(Proposed Device)	ROMA (HE4 EIA +ARCHITECT CA 125 II)(Predicate Device)K103358
Instrument System	LUMIPULSE G1200 Only	Manual ELISA for HE4 andARCHITECT i2000SR forCA125
Assay Format	Same immunoassay platformfor the detection of HE4 andCA125 in a single sample	Separate immunoassayplatforms for the detection ofHE4 and CA125 in a singlesample
HE4 Measuring Range	The measuring interval of theLumipulse G HE4 assay is20.0 pmol/L to 1500.0 pmol/L.	The measuring interval of theHE4 EIA is between 15 and900 pM.
Type of Specimen	Human Serum and Plasma(lithium heparin ordipotassium EDTA)	Human Serum

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Standard/Guidance Document Referenced (if applicable):

. CLSI EP5-A3- Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
CLSI EP7-A2 Interference Testing in Clinical Chemistry: Approved Guideline-Second . Edition
CLSI EP28-A3C Defining, Establishing, and Verifying Reference Intervals in the Clinical . Laboratory; Approved Guideline-Third Edition
CLSI EP9-A3 - Measurement Procedure Comparison and Bias Estimation Using Patient Samples; approved Guideline - Third Edition
Guidance document entitled "Class II Special Controls Guidance Document: Ovarian ● Adnexal Mass Assessment Score Test System"
Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover . Human Specimens that are Not Individually Identifiable - Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff
. FDA Guidance Document - Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices (May 11, 2005)

Test Principle:

Lumipulse G HE4 is an assay system, including a set of immunoassay reagents, for the quantitative measurement of HE4 in specimens based on CLEA technology by a two-step sandwich immunoassay method on the LUMIPULSE G1200 System. HE4 in specimens specifically binds to anti-HE4 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-HE4 monoclonal antibody (mouse) specifically binds to HE4 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 generated by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of HE4.

Lumipulse G CA125Il is an assay system, including a set of immunoassay reagents, for the quantitative measurement of CA125 in specimens based on CLEA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System. CA125 in specimens specifically binds to anti-CA125 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-CA125 monoclonal antibody (mouse) specifically binds to CA125 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 generated by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of CA125.

The Lumipulse G ROMA Calculator Tool will be used for calculating the ROMA score. Using and the value of the 2 analytes, Lumipulse G ROMA scores (numerical score from 0.00-10.00)

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for both premenopausal and postmenopausal will be calculated and will indicate whether a woman is at low likelihood or high likelihood for finding malignancy on surgery. Both premenopausal and postmenopausal Lumipulse G ROMA results will be reported to the ordering physician who will decide which result to use based on patient's menopausal status.

Performance Characteristics (if/when applicable):

Both Lumipulse G HE4 and Lumipulse G CA125II are previously cleared devices. Analytical performance for Lumipulse G HE4 and Lumipulse G CA125II were validated in K151378 and K142895 respectively. There has been no modification of assay methods for Lumipulse G HE4 and Lumipulse G CA125II since the original clearance for each assay.

Data were generated using the LUMIPULSE G1200 System.

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

Lot-to-Lot Precision

A study was performed as described per the National Committee for Clinical Laboratory Standards NCCLS (CLSI) guideline EP5-A3. A panel of five serum samples was tested and evaluated using both premenopausal and postmenopausal forms of the ROMA equation, using three lots of Lumipulse G HE4 Reagent Kits and three lots of Lumipulse G CA 125 II Reagent Kits, evaluating two measurements of each panel, at two separate times per day for 10 days. Data from this study is summarized in the following tables.

Summary for the Lot-to-Lot Variability Premenopausal ROMA Score (N=120 for each nanel)

panel)
		Between Lots		Between DaysWithin Lots		Between-RunsWithin DaysWithin Lot		Within Runs		Total
Sample	Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	1.02	0.031	3.0	0.022	2.2	0.018	1.7	0.021	2.1	0.047	4.6
Panel 2	1.87	0.054	2.9	0.033	1.8	0.041	2.2	0.036	2.0	0.084	4.5
Panel 4	4.04	0.091	2.3	0.049	1.2	0.041	1.0	0.070	1.7	0.131	3.3
Panel 5	8.75	0.059	0.7	0.013	0.2	0.037	0.4	0.034	0.4	0.078	0.9
Panel 6	9.94	0.001	0.0	0.000	0.0	0.002	0.0	0.003	0.0	0.003	0.0

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Summary for the Lot-to-Lot Variability for Postmenopausal ROMA Score (N=120 for each nall

		Between Lots			Between DaysWithin Lots		Between-RunsWithin DaysWithin Lot		Within Runs		Total
Sample	Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	1.55	0.006	0.4	0.026	1.7	0.014	0.9	0.021	1.4	0.038	2.4
Panel 2	3.16	0.017	0.5	0.037	1.2	0.032	1.0	0.036	1.1	0.063	1.7
Panel 4	5.71	0.028	0.5	0.033	0.6	0.038	0.7	0.039	0.7	0.070	1.2
Panel 5	8.81	0.018	0.2	0.012	0.1	0.021	0.2	0.016	0.2	0.034	0.4
Panel 6	9.80	0.004	0.0	0.002	0.0	0.003	0.0	0.004	0.0	0.007	0.1

Reproducibility

A study was performed as described per the National Committee for Clinical Laboratory Standards NCCLS (CLSI) guideline EP5-A2. A panel of five serum samples was tested and evaluated using both premenopausal and postmenopausal forms of the ROMA equation, using one lot of Lumipulse G HE4 Reagent Kits and one lot of Lumipulse G CA 125 II Reagent Kits, at three sites, evaluating two measurements of each panel, at two separate times per day for 10 days. Data from this study is summarized in the following tables.

Summary for the Site-to-Site Variability for Premenopausal ROMA Score (N=120 for each panel)

		Between Sites		Between DaysWithin Sites		Between-RunsWithin DaysWithin Lot		Within Runs		Total
Sample	Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	1.01	0.067	6.7	0.024	2.4	0.030	3.0	0.026	2.6	0.081	8.1
Panel 2	1.86	0.109	5.8	0.042	2.3	0.062	3.4	0.033	1.8	0.136	7.3
Panel 4	4.01	0.176	4.4	0.100	2.5	0.119	3.0	0.075	1.9	0.246	6.1
Panel 5	8.75	0.094	1.1	0.022	0.3	0.086	1.0	0.026	0.3	0.132	1.5
Panel 6	9.94	0.007	0.1	0.003	0.0	0.004	0.0	0.003	0.0	0.009	0.1

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Summary for the Site-to-Site Variability for Postmenopausal ROMA Score (N=40 for each nanel)

panel)
		Between Sites		Between DaysWithin Sites		Between-RunsWithin DaysWithin Lot		Within Runs		Total
Sample	Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Panel 1	1.51	0.063	4.2	0.029	1.9	0.023	1.6	0.026	1.8	0.078	5.2
Panel 2	3.11	0.109	3.5	0.052	1.7	0.052	1.7	0.033	1.1	0.136	4.4
Panel 4	5.63	0.118	2.1	0.067	1.2	0.082	1.5	0.043	0.8	0.164	2.9
Panel 5	8.77	0.059	0.7	0.021	0.2	0.056	0.6	0.015	0.2	0.085	1.0
Panel 6	9.79	0.014	0.1	0.006	0.1	0.010	0.1	0.004	0.0	0.019	0.2

b. Linearity/assay reportable range:
Not applicable
Traceability, Stability, Expected values (controls, calibrators, or methods): C.
Each assay uses its own calibrators.

Lumipulse G CA125II Calibrators

The Lumipulse G CA125II Calibrators are for the use in the calibration of the LUMIPULSE G System for the quantitative measurement of CA125 in serum or plasma (sodium heparin, lithium heparin, and dipotassium EDTA).

The OC125 defined antigen is used in the LUMIPULSE G CA125II Calibrators. This material is obtained from Fujirebio Diagnostics, Inc. proprietary human ovarian carcinoma cell line.

Lumipulse G HE4 Calibrators

The Lumipulse G HE4 Calibrators are for the use in the calibration of the LUMPULSE G System for the quantitative measurement of HE4 in serum or plasma (lithium heparin and dipotassium EDTA).

The HE4 antigen is used in the Lumipulse G HE4 Calibrators. This material is provided by Fujirebio Diagnostics, AB. The Lumipulse G HE4 assay is standardized against the Fujirebio Diagnostics HE4 EIA.

Stabilitv

Specimen:

Lumipulse G ROMA is intended for use with serum and plasma (lithium heparin and dipotassium EDTA). The specimen stability and storage claims are limited to the Lumipulse G HE4 assay. Samples can be stored at 2-8°C for 3 days or at -10°C or colder for up to 1 month before being tested.

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Calibration Curve: For Lumipulse G HE4 and Lumipulse G CA125II, the calibration curve is stable up to 30 days.

Users are instructed to refer to the individual stability information in the package insert of each assay.

Lumipulse G HE4 when stored at 2-10℃ is stable until the expiration date stated on the label outside of the kit box. The current shelf life of Lumipulse G HE4 is 8 months.

Lumipulse G CA125Il when stored at 2-10℃ is stable until the expiration date stated on the label outside of the kit box. The current shelf life of Lumipulse G CA125Il is 10 months.

Kit	Stability
Lumipulse G CA125IIImmunoreaction Cartridge	2-10°C for 10 months
Lumipulse G CA125IICalibrators	2-10°C for 10 months
Lumipulse G HE4Immunoreaction Cartridge	2-10°C for 8 months
Lumipulse G HE4Calibrators	2-10°C for 8 months

d. Detection limit:

The limits of detection and limits of quantitation reported in each assay's package insert are incorporated into the algorithm such that results outside of the measuring interval are not imported and do not yield a Lumipulse G ROMA score.

e. Analytical specificity:

Studies were performed based on guidance from CLSI Document EP7-A2. Potential interferents were evaluated to determine whether premenopausal (Pre) and postmenopausal (Post) ROMA scores were affected when using Lumipulse G ROMA. The potential interferents listed in the table below were spiked into 4 serum panels. The samples were assayed, and the ROMA scores of the spiked samples were compared to reference samples.

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Mean (%) percent differences of Pre and Post-Menopausal Lumipulse G ROMA Scores for
endogenous interferents.

Interferent	TestConcentration	Mean Percent (%)DifferencePre-MenopausalROMA	Mean Percent (%)DifferencePost-MenopausalROMA
Free Bilirubin (Unconjugated)	60.0 mg/dL	0%	0%
Bilirubin (Conjugated)	60.0 mg/dL	1%	0%
Triglycerides(Intralipid 20% Emulsion)	3,000 mg/dL	1%	-1%
Hemoglobin	500 mg/dL	0%	0%
Total Protein(Human Serum Albumin)	12 g/dL	-1%	-1%
Immunoglobulin G (IgG)	5 g/dL	-2%	-1%
Biotin	19.8 mg/dL	0%	0%
Human Anti-Mouse Antibodies(HAMA)	1000 ng/mL	-1%	0%
Rheumatoid Factor (RF)	1000 IU/mL	1%	0%

f. Assay cut-off:
See Clinical Cutoff in M (4) below
1. Comparison studies:
- a. Method Comparison

Lumipulse G ROMA method comparison study was performed on the LUMIPULSE G1200 System using specimens consistent with CLSI guideline EP9-A3. The weighted Deming regression method was used to compare Lumipulse G ROMA to ROMA (HE4 EIA + ARCHITECT CA 125 II). The data are summarized in the following table.

Lumipulse G ROMA vs. ROMA (HE4 EIA + ARCHITECT CA 125 II)Premenopausal Women
Lumipulse G ROMAScore	n	CorrelationCoefficient(r)	Intercept(95% CI*)	Slope(95% CI*)
0.32 - 9.99	53	0.9977	-0.004(-0.085, 0.078)	1.005(0.994, 1.016)

*CI = Confidence Interval

Lumipulse G ROMA vs. ROMA (HE4 EIA + ARCHITECT CA 125 II) Postmenopausal Women

Lumipulse G ROMAScore	n	CorrelationCoefficient(r)	Intercept(95% CI*)	Slope(95% CI*)
0.57 - 10.00	115	0.9953	-0.103	0.999
			(-0.254, 0.047)	(0.931, 1.016)

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*CI = Confidence Interval

b. Matrix Comparison

Lumipulse G ROMA on the LUMIPULSE G1200 System was evaluated for matrix differences by performing a study using eighty six (86) matched sets of serum and Kر EDTA plasma samples. The results demonstrated equivalency between the matrices and are presented as a regression equation in the following table:

MatrixComparison	n	ROMAEquation	ROMA Range	Regression Equation andCorrelation Coefficient
Serum vsK2 EDTA Plasma	86	Premenopausal	0.33 - 9.93	y= 1.001(x) - 0.072;r=0.9983
Serum vsK2 EDTA Plasma	86	Postmenopausal	0.38 - 9.78	y= 1.004(x) - 0.058;r=0.9988

3. Clinical studies:

a. Clinical sensitivitv:

See 3(c) below

b. Clinical specificity:
See 3(c) below
c. Other clinical supportive data (when a. and b. are not applicable):

Risk of Ovarian Malignancy Algorithm (ROMA) in Patients Presenting with an Adnexal Mass

Lumipulse G ROMA takes into account the results of Lumipulse G HE4 and the results of Lumipulse G CA125Il as well as the menopausal status of the woman. The Lumipulse G ROMA value is used to aid in assessing whether a woman is at high or low likelihood of finding malignancv on surgery.

The effectiveness of Lumipulse G ROMA was determined in a prospective, multi-center, blinded clinical trial for premenopausal and postmenopausal women presenting with an adnexal mass requiring surgical intervention.

A total of 450 women were evaluable in the study. For each patient, an initial cancer risk assessment (ICRA) was completed by a non-gynecological oncologist, providing the assessment of the patient's mass as benign (negative) or malignant (positive) based upon the information available to the non-gynecological oncologist during their work-up of the patient. The corresponding histopathology reports were collected after surgery.

Using a preoperatively collected serum sample, Lumipulse G ROMA was determined and the patient was stratified into a low or a high likelihood group for finding malignancy on surgery.

The histopathological classifications of the 450 evaluable patients are summarized in the following table:

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HistopathologicalClassification	Totaln = 450		Premenopausaln = 244		Postmenopausaln = 206
	N	%	N	%	N	%
Benign Pathology	366	81.3	223	91.4	143	69.4
Low Malignant Potential(LMP) Borderline	18	4.0	7	2.9	11	5.3
Epithelial Ovarian Cancer	47	10.4	9	3.7	38	18.4
Non-Epithelial OvarianCancer	2	0.4	0	0.0	2	1.0
Other GynecologicCancer	9	2.0	3	1.2	6	2.9
Other Cancer	7	1.6	1	0.4	6	2.9
Metastatic Cancer	1	0.2	1	0.4	0	0.0

Use of Lumipulse G ROMA for stratification into low likelihood and high likelihood groups for finding malignancy on surgery

The following cut-points are used:

Premenopausal women

Lumipulse G ROMA score ≥ 1.31 = High likelihood of finding malignancy

Lumipulse G ROMA score < 1.31 = Low likelihood of finding malignancy

Postmenopausal women

Lumipulse G ROMA score ≥ 2.77= High likelihood of finding malignancy

Lumipulse G ROMA score < 2.77 = Low likelihood of finding malignancy

The reported result should include both the premenopausal and postmenopausal likelihood result and associated Lumipulse G ROMA score on a scale of 0.00-10.00.

The stratification of patients presenting with an adnexal mass into high likelihood of harboring malignant disease (epithelial ovarian cancer (EOC), borderline or low malignant potential (LMP) tumors and other gynecological or non-gynecological cancers) using Lumipulse G ROMA results above the cut-point ≥ 1.31 for premenopausal and ≥ 2.77 for postmenopausal women by histopathology is shown in the table below:

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	Premenopausal	Postmenopausal	Total
	n = 244	n = 206	n = 450
All EOC1	100.0%(9/9)	92.1%(35/38)	93.6%(44/47)
EOC Stage I + II	100.0%(3/3)	66.7%(6/9)	75.0%(9/12)
EOC Stage III + IV	100.0%(5/5)	100.0%(28/28)	100.0%(33/33)
LMP Tumors	57.1%(4/7)	81.8%(9/11)	72.2%(13/18)
Other Cancer2	40.0%(2/5)	71.4%(10/14)	63.2%(12/19)
All Cancer and LMPTumors	71.4%(15/21)	85.7%(54/63)	82.1%(69/84)

1 2 EOC patients were unstaged

2 non-epithelial ovarian cancer, other gynecologic, non-gynecologic and metastatic cancers.

The performance of Lumipulse G ROMA for stratification into low likelihood and high likelihood groups for premenopausal and postmenopausal women with epithelial ovarian cancer (EOC) only is shown in the table below:

	Premenopausaln = 232		Postmenopausaln = 181
	Estimate	95% CI1	Estimate	95% CI1
Sensitivity	100.0%(9/9)	70.1%, 99.2%	92.1%(35/38)	79.2%, 97.2%
Specificity	74.9%(167/223)	68.8%, 80.1%	77.6%(111/143)	70.1%, 83.7%
TP-FP2	74.9%	69.1%, 80.7%	69.7%	58.5%, 80.9%
PPV3	13.8%(9/65)	7.5%, 24.2%	52.2%(35/67)	40.5%, 63.7%
NPV4	100.0%(167/167)	97.8%, 99.9%	97.4%(111/114)	92.5%, 99.1%
Prevalence		3.9% (9/232)		21.0% (38/181)

1Confiiidence Interval

²TP-FP = True Positive rate – False Positive rate

³PPV = Positive Predictive Value

4NPV = Negative Predictive Value

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Adjunctive use of Lumipulse G ROMA with Initial Cancer Risk Assessment (ICRA) for stratification into low likelihood and high likelihood groups of harboring malignancy The performance for the adjunctive use of Lumipulse G ROMA with ICRA (Lumipulse G ROMA and/or ICRA being positive for high likelihood of finding malignancy on surgery) was evaluated by calculating sensitivity, PPV (positive predictive value) and NPV (negative predictive value). Adding Lumipulse G ROMA to ICRA produced a statistically significant improvement in the negative predictive value. The NPV for correctly classifying benign patients into the low likelihood group increased from 93.1% to 96.1%, making the use of Lumipulse G ROMA with ICRA effective in ruling out malignancy.

Malignancy by Pathology				No Malignancy by Pathology
		ICRA					ICRA
		Positive(HighLikelihood)	Negative(LowLikelihood)	Total			Positive(HighLikelihood)	Negative(LowLikelihood)	Total
ROMA	Positive(HighLikelihood)	56	13	69	ROMA	Positive(HighLikelihood)	27	61	88
	Negative(LowLikelihood)	5	10	15			Negative(LowLikelihood)	31	247
	Total	61	23	84		Total	58	308	366

Total counts for premenopausal and postmenopausal women combined:

1 All malignancies found including EOC, LMP, non-epithelial ovarian cancer, other gynecologic and non-gynecologic cancers.

Performance for premenopausal and postmenopausal women combined with 95% Confidence Intervals (CI):

	ICRA			Lumipulse G ROMA		Adjunctive
	Estimate	95% CI	Estimate	95% CI	Estimate	95% CI
Sensitivity	72.6%(61/84)	62.3%, 81.0%	82.1%(69/84)	72.6%, 88.8%	88.1%(74/84)	79.5%, 93.4%
Specificity	84.2%(308/366)	80.1%, 87.5%	76.0%(278/366)	71.3%, 80.0%	67.5%(247/366)	62.5%, 72.1%
TP-FP1	56.8%	46.3%, 67.2%	58.1%	48.6%, 67.6%	55.6%	47.0%, 64.2%
PPV2	51.3%(61/119)	42.4%, 60.0%	43.9%(69/157)	36.4%, 51.8%	38.3%(74/193)	31.8%, 45.4%
NPV3	93.1%(308/331)	89.8%, 95.3%	94.9%(278/293)	91.7%, 96.9%	96.1%(247/257)	93.0%, 97.9%
Prevalence	18.7% (84/450)

TP-FP = True Positive rate - False Positive rate

2PPV = Positive Predictive Value

3NPV = Negative Predictive Value

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Image /page/19/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized blue and white graphic on the left, resembling a water droplet or a stylized letter 'F'. To the right of the graphic, the text "FUJIREBIO" is displayed in a bold, sans-serif font, with "Diagnostics, Inc." appearing in a smaller font size below it. The overall design is clean and professional, conveying a sense of scientific expertise and corporate identity.

4. Clinical cut-off:

The following cut-offs are used to interpret the result. The Lumipulse G ROMA score is between 0.00 and 10.00.

Premenopausal women: ROMA score ≥1.31 High likelihood of finding malignancy ROMA score <1.31 Low likelihood of finding malignancy Postmenopausal women: ROMA score ≥2.77 High likelihood of finding malignancy ROMA score <2.77 Low likelihood of finding malignancy

Expected values/Reference range:

The distribution of Lumipulse G ROMA determined in 120 healthy premenopausal women and 118 healthy postmenopausal women is shown in the table below:

	AllHealthySubjects	PremenopausalHealthySubjects	PostmenopausalHealthySubjects
N	238	120	118
Lumipulse G ROMA Result
Mean	0.97	0.85	1.10
(SD)	(0.79)	(1.00)	(0.49)
Median	0.83	0.65	0.99
Range (min - max)	0.23-9.92	0.23-9.92	0.38-2.94
Reference Interval(5th - 95th percentile)	0.33-1.98	0.29-1.73	0.52-2.03
Lumipulse G ROMA Likelihood (n, %)
High Likelihood	17 (7.1%)	15 (12.5%)	2 (1.7%)
Low Likelihood	221 (92.9%)	105 (87.5%)	116 (98.3%)

In this study, 95% of the premenopausal healthy female subjects had Lumipulse G ROMA results equal to or below 1.73 and 95% of the postmenopausal healthy female subjects had Lumipulse G ROMA results equal to or below 2.03.

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The distribution of Lumipulse G ROMA in premenopausal women with nonovarian malignancy conditions is shown in the table below:

	EpithelialOvarianCancer	Endo-metrialCancer	BreastCancer	GICancer	LungCancer	BladderCancer
N	154	40	40	40	40	40
Lumipulse G ROMA Result
Mean	7.63	3.19	2.90	2.60	3.89	3.23
(SD)	(2.83)	(2.26)	(2.47)	(1.75)	(2.42)	(2.24)
Median	9.19	2.14	1.76	1.91	3.88	2.46
Range (min - max)	0.16-10.0	1.11-9.54	0.48-9.81	0.6-8.04	0.51-9.8	0.64-9.96
Reference Interval(5th - 95th percentile)	1.90-9.98	1.20-7.53	0.53-8.65	0.70-5.97	0.58-8.40	0.93-7.04
Lumipulse G ROMA Likelihood (n, %)
High Likelihood	143 (92.9%)	18 (45.0%)	16(40.0%)	16 (40.0%)	27 (67.5%)	17 (42.5%)
Low Likelihood	11 (7.1%)	22 (55.0%)	24(60.0%)	24 (60.0%)	13 (32.5%)	23 (57.5%)

The distribution of Lumipulse G ROMA in premenopausal and postmenopausal women with benign conditions is shown in the table below:

	BenignGynecologic	BenignNon-Gynecologic	Pregnant	CongestiveHeartFailure	Hypertension
N	366	40	40	40	40
Lumipulse G ROMA Result
Mean	1.49	2.22	0.64	3.72	3.52
(SD)	(1.20)	(2.10)	(0.26)	(2.06)	(3.06)
Median	1.09	1.57	0.58	3.71	1.99
Range (min - max)	0.17-8.47	0.58-9.99	0.28-1.57	0.22-7.78	0.43-10
Reference Interval(5th - 95th percentile)	0.41-3.82	0.67-4.84	0.31-1.02	0.71-7.18	0.57-9.56
Lumipulse G ROMA Likelihood (n, %)
High Likelihood	89 (24.3%)	9 (22.5%)	1 (2.5%)	24 (60.0%)	20 (50.0%)
Low Likelihood	277 (75.7%)	31 (77.5%)	39 (97.5%)	16 (40.0%)	20 (50.0%)

It is recommended that each laboratory establish its own reference value for the population of interest.

Proposed Labeling:

The labeling satisfies the requirements of 21 CFR Part 809.10.

Conclusion:

The results of these analytical) and clinical studies demonstrate that Lumipulse G ROMA is substantially equivalent to the performance of ROMA (HE4 EIA + ARCHITECT CA 125 II).

Regulation Number and Section

§ 866.6050 Ovarian adnexal mass assessment score test system.

(a)
Identification. An ovarian/adnexal mass assessment test system is a device that measures one or more proteins in serum or plasma. It yields a single result for the likelihood that an adnexal pelvic mass in a woman, for whom surgery is planned, is malignant. The test is for adjunctive use, in the context of a negative primary clinical and radiological evaluation, to augment the identification of patients whose gynecologic surgery requires oncology expertise and resources.(b)
Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Ovarian Adnexal Mass Assessment Score Test System.” For the availability of this guidance document,see § 866.1(e).(c)
Black box warning. Under section 520(e) of the Federal Food, Drug, and Cosmetic Act these devices are subject to the following restriction: A warning statement must be placed in a black box and must appear in all advertising, labeling, and promotional material for these devices. That warning statement must read: