ARCHITECT Risk of Ovarian Malignancy Algorithm (ROMA) is a qualitative serum test that combines the results of ARCHITECT HE4. ARCHITECT CA 125 II and menopausal status into a numerical score.

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

Device Description

ARCHITECT ROMA is a qualitative serum test that combines the results of 2 analytes, HE4 (ARCHITECT HE4) and CA125 (ARCHITECT CA 125 II) and menopausal status into a numerical score between 0.0 and 10.0. The premenopausal status must be based on ovarian function determined with information available from clinical evaluation and medical history.

The test system consists of the ARCHITECT HE4 assay, the ARCHITECT CA 125 Il assay and the ARCHITECT i2000SR. The ARCHITECT i2000SR is capable of calculating the ROMA score. The immunoassays are performed according to the directions detailed in each product insert.

AI/ML Overview

This document describes the ARCHITECT ROMA, a qualitative serum test that combines results of ARCHITECT HE4, ARCHITECT CA 125 II, and menopausal status to provide a numerical score. It aims to assess the likelihood of malignancy in women with an ovarian adnexal mass for whom surgery is planned.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly laid out as distinct "criteria" with corresponding "acceptance values" in the provided document. Instead, the document presents clinical performance metrics, specifically sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for both standalone ROMA and its adjunctive use with Initial Cancer Risk Assessment (ICRA). The tables below summarize the reported device performance for these key metrics.

Standalone ARCHITECT ROMA Performance for Stratification into Likelihood of Finding Malignancy on Surgery

(Based on N=238 Premenopausal and N=184 Postmenopausal women, identifying Epithelial Ovarian Cancer, EOC)

Metric	Premenopausal Performance (95% CI)	Postmenopausal Performance (95% CI)
Sensitivity	100.0% (70.1, 99.2)	92.3% (79.7, 97.2)
Specificity	86.5% (81.4, 90.3)	85.5% (78.9, 90.3)
PPV	22.5% (12.3, 37.4)	63.2% (50.2, 74.4)
NPV	100.0% (98.1, 99.9)	97.6% (93.3, 99.2)
Prevalence	3.8%	21.2%

Adjunctive Use of ARCHITECT ROMA with ICRA Performance

(Based on N=85 Malignancies and N=374 No Malignancy, covering EOC, LMP, non-epithelial ovarian cancer, other gynecologic, and non-gynecologic cancers)

Metric	ICRA Performance (95% CI)	ARCHITECT ROMA Performance (95% CI)	Adjunctive Performance (95% CI)
Sensitivity	72.9% (62.7, 81.2)	80.0% (70.3, 87.1)	87.1% (78.3, 92.6)
Specificity	84.2% (80.2, 87.6)	86.1% (82.2, 89.2)	75.7% (71.1, 79.7)
PPV	51.2% (42.4, 60.0)	56.7% (47.7, 65.2)	44.8% (37.5, 52.5)
NPV	93.2% (90.0, 95.4)	95.0% (92.1, 96.8)	96.3% (93.4, 97.9)
Prevalence	18.5%	18.5%	18.5%

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

Sample Size for Clinical Study (Test Set):
- Total: 459 women
- Premenopausal: 250
- Postmenopausal: 209
- For the performance tables (sensitivity, specificity, etc.):
  - Premenopausal: 238
  - Postmenopausal: 184
  - Adjunctive use: 459 (85 malignancies, 374 no malignancy)
Data Provenance: The study was a "prospective, multi-center, blinded clinical trial." The country of origin is not explicitly stated, but the submission is to the US FDA, implying data collected for a US market, potentially including US sites.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document states that "The corresponding histopathology reports were collected after surgery" for each patient to determine the truth (benign or malignant). It does not specify the number of individual experts (e.g., pathologists) involved in establishing the histopathological ground truth or their specific qualifications (e.g., years of experience). However, histopathological classification is a standard and well-established method for confirming benign or malignant status in medical practice.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method for discrepancies in ground truth or interpretation of results. The ground truth was established by "histopathology reports," which typically represent a definitive diagnosis.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and 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 focusing on human reader improvement with AI assistance was not explicitly detailed in this document. The study evaluated the adjunctive use of ARCHITECT ROMA with ICRA (Initial Cancer Risk Assessment, which is typically a clinical and radiological assessment performed by human experts).

The document states: "Adjunctive use ARCHITECT ROMA with ICRA produced a statistically significant improvement in the negative predictive value (NPV). The NPV for correctly classifying benign patients into the low likelihood group increased from 93.2 to 96.3%, making the adjunctive use of ARCHITECT ROMA with ICRA effective in ruling out malignancy."

While this shows an improved performance metric (NPV) when ARCHITECT ROMA is used in conjunction with ICRA, it does not quantify human reader performance with and without AI assistance in an MRMC setting. It rather compares the performance of ICRA alone versus ICRA plus ROMA.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, a standalone performance evaluation of ARCHITECT ROMA was conducted. The table "Stratification of 422 women... into low likelihood and high likelihood groups for finding malignancy on surgery using ARCHITECT ROMA" directly reports the sensitivity, specificity, PPV, and NPV of the ARCHITECT ROMA algorithm alone, without explicit human-in-the-loop assessment beyond the initial patient selection criteria.

7. The Type of Ground Truth Used

The primary ground truth used for the clinical study was histopathology reports collected after surgery, classifying ovarian adnexal masses as benign or malignant.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for the training set used to develop the ARCHITECT ROMA algorithm itself. It mentions that ARCHITECT HE4 and ARCHITECT CA 125 II are "previously cleared devices" and their analytical performance was validated separately. The clinical study described in this document serves as a validation or test set for the combined ARCHITECT ROMA algorithm, rather than a training set for its development. The algorithm's equations are provided, indicating it was developed and fixed prior to this validation study.

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

Since the clinical study described is a validation study and not a development study for the algorithm, the document does not provide details on how the ground truth for an initial training set (if any, for the specific ROMA algorithm) was established. It's plausible the algorithm was developed using a separate dataset, or by leveraging data from the original ROMA™ (HE4 EIA + ARCHITECT CA 125 II) predicate device (K103358), which also used "histopathological findings" as ground truth in its own studies.

Summary

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

May 2, 2016

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

Re: K151502

Trade/Device Name: ARCHITECT ROMA Regulation Number: 21 CFR 866.6050 Regulation Name: Ovarian adnexal mass assessment score test system Regulatory Class: II Product Code: ONX Dated: April 18, 2016 Received: April 19, 2016

Dear Ms. Dickson:

This letter corrects our substantially equivalent letter of April 28, 2016.

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

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

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

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) K151502

Device Name ARCHITECT ROMA

Indications for Use (Describe)

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

ARCHITECT Risk of Ovarian Malignancy Algorithm (ROMA) is a qualitative serum test that combines the results of ARCHITECT HE4. ARCHITECT CA 125 II and menopausal status into a numerical score.

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

X Prescription Use (Part 21 CFR 801 Subpart D)

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

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

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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.

A. 510(k) Number:

K151502

B. Purpose for Submission:

New device

C. Measurand:

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

D. Type of Test:

Software algorithm and 2 immunoassays

E. Applicant:

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

Summary preparation date: April 18, 2016

F. Proprietary and Established Names:

ARCHITECT ROMA

G. Regulatory Information:

1. Regulation section: 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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Image /page/4/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a blue abstract symbol on the left, followed by the company name in blue text. The word "FUJIREBIO" is in a larger, bolder font than "Diagnostics, Inc."

H. Intended Use:

1. Intended use(s): For In Vitro Diagnostic Use Only.
  ARCHITECT Risk of Ovarian Malignancy Algorithm (ROMA'") is a qualitative serum test that combines the results of ARCHITECT HE4, ARCHITECT CA 125 II™ and menopausal status into a numerical score.

ARCHITECT 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. ARCHITECT 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. ARCHITECT 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: ARCHITECT 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 ARCHITECT ROMA carries the risk of unnecessary testing, surgery, and/or delaved diagnosis.

1. Indication(s) for use: Same as Intended Use.
1. Special conditions for use statement(s): Prescription use only
1. Special instrument requirements: ARCHITECT i2000SR system

I. Device Description:

Both ARCHITECT HE4 and ARCHITECT CA 125 II are previously 510(k) cleared Class II devices (K093957 and K042731 respectively). The ARCHITECT HE4 assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of HE4 antigen in human serum. 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

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Image /page/5/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic element on the left, consisting of blue and green shapes resembling a water droplet or a stylized letter. To the right of the graphic is the text "FUJIREBIO" in a bold, blue sans-serif font, with the registered trademark symbol next to it. Below "FUJIREBIO" is the text "Diagnostics, Inc." in a smaller, black sans-serif font.

ovarian cancer. ARCHITECT CA 125 II assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of CA125 reactive determinants in human serum and plasma on the ARCHITECT i System and was previously cleared as an aid in monitoring response to therapy for patients with epithelial ovarian cancer.

Using an algorithm and the value of the 2 analytes, ARCHITECT ROMA scores (numerical score from 0.0-10.0) for both premenopausal and postmenopausal will be calculated and indicate a low likelihood or high likelihood for finding malignancy on surgery.

J. 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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Image /page/6/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized graphic on the left, featuring blue and white shapes, followed by the company name in blue text. The word "FUJIREBIO" is in a larger, bolder font, and "Diagnostics, Inc." is in a smaller font below it. A registered trademark symbol is located to the right of the word "FUJIREBIO".

Similarities
	ARCHITECT ROMA(Proposed Device)	ROMA (HE4 EIA +ARCHITECT CA 125 II)(Predicate Device)K103358
Device TypeClassification	In vitro diagnosticClass II	In vitro diagnosticClass 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	ARCHITECT Risk of OvarianMalignancy Algorithm(ROMATM) is a qualitativeserum test that combines theresults of ARCHITECT HE4,ARCHITECT CA 125 IITM andmenopausal status into anumerical score.ARCHITECT ROMA isintended to aid in assessingwhether a premenopausal orpostmenopausal woman whopresents with an ovarianadnexal mass is at high orlow likelihood of findingmalignancy on surgery.ARCHITECT ROMA isindicated for women whomeet the following criteria:over age 18; ovarian adnexalmass present for whichsurgery is planned, and notyet referred to an oncologist.ARCHITECT 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(ROMATM) is a qualitativeserum test that combines theresults of HE4 EIA,ARCHITECT CA 125 IITM andmenopausal status into anumerical 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.
Black box warning(PRECAUTION)	Should not be used withoutan independent clinical(radiological evaluation and is	Should not be used withoutan independent clinical(radiological evaluation and is
Similarities
	ARCHITECT ROMA(Proposed Device)	ROMA (HE4 EIA +ARCHITECT CA 125 II)(Predicate Device)K103358
Specimen CollectionMethod	Routine PhlebotomyTechniques	Routine PhlebotomyTechniques
Type of Specimen	Human Serum	Human Serum
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:ARCHITECT ROMA score ≥1.31 = High likelihood offinding malignancyARCHITECT ROMA score <1.31= Low likelihood offinding malignancyPostmenopausal:ARCHITECT ROMA score ≥2.77 = High likelihood offinding malignancyARCHITECT 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
Differences
	ARCHITECT ROMA(Proposed Device)	ROMA (HE4 EIA +ARCHITECT CA 125 II)(Predicate Device)K103358
Instrument System	ARCHITECT i2000SR Only	Manual ELISA for HE4 andARCHITECT i2000SR froCA125
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 theARCHITECT HE4 assay is20.0 pmol/L to 1500.0 pmol/L.	The measuring interval of theHE4 EIA is between 15 and900 pM.
Software	Provided on the ARCHITECTi2000SR for automated entryof assay values to obtainresult	Provided as separate CD-ROM for manual entry ofassay values to obtain result
Sample Volume	75µL per reportable HE4 testresult (singlicate)75µL per reportable CA125test result (singlicate)	50µL per reportable HE4 testresult (duplicate)75µL per reportable CA125test result (singlicate)
Software	ARCHITECT i2000SR willhave the capability to producethe ROMA result	Manual entry of assay valuesusing software on a PersonalComputer (PC) to producethe ROMA result

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Image /page/7/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 or a stylized leaf. To the right of the graphic, the text "FUJIREBIO" is displayed in a bold, blue sans-serif font, with the registered trademark symbol (®) next to it. Below "FUJIREBIO", the words "Diagnostics, Inc." are written in a smaller, black sans-serif font.

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Image /page/8/Picture/1 description: The image contains the logo for Fujirebio Diagnostics, Inc. The logo features a stylized graphic element on the left, consisting of blue and white shapes with vertical lines. To the right of the graphic is the company name, "FUJIREBIO," in a bold, blue sans-serif font. Below the company name is the text "Diagnostics, Inc." in a smaller, black sans-serif font.

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Image /page/9/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized symbol on the left and the company name on the right. The symbol is a combination of blue and green shapes, with a white teardrop shape in the center. The company name is written in blue, with "FUJIREBIO" on the top line and "Diagnostics, Inc." on the bottom line.

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

. CLSI EP5-A2 - Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline - Second Edition
. CLSI EP7-A2 - Interference Testing in Clinical Chemistry; Approved Guideline-Second Edition
CLSI C28-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)

L. Test Principle:

The ARCHITECT HE4 assay is a two-step immunoassay for the quantitative determination of HE4 antigen in human serum using chemiluminescent microparticle immunoassay (CMIA) technology with flexible assay protocols, referred to as Chemiflex. In the first step, sample and anti-HE4 coated paramagnetic microparticles are combined. HE4 antigen present in the sample binds to the anti-HE4 coated microparticles. After washing, acridinium-labeled anti-HE4 conjugate is added. Following another wash cycle, pre-trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs). A direct relationship exists between the amount of HE4 antigen in the sample and the RLUs detected by the ARCHITECT i System optics.

The ARCHITECT CA 125 II assay is a two-step sandwich technique immunoassay to determine the presence of OC 125 defined antigen in human serum and plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex. In the first step of the assay, sample and antibody (mouse monoclonal anti-OC 125) coated paramagnetic microparticles are combined. CA125 reactive determinants present in the sample bind to the antibody coated microparticles. After washing, a second acridinium-labeled antibody conjugate is added in the second step. Pre-Trigger and Trigger Solutions are then added to the reaction mixture; the resulting chemiluminescent reaction is measured as relative light units (RLUs). A direct relationship exists between the amount of CA125 reactive determinants in the sample and the RLUs detected by the ARCHITECT™ i optical system.

The ARCHITECT i2000SR is capable of calculating the ROMA score. Using and the value of the 2 analytes, ARCHITECT ROMA scores (numerical score from 0.0-10.0) 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 ARCHITECT ROMA results will be reported to the ordering physician who will decide which result to use based on patient's menopausal status.

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Image /page/10/Picture/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized blue and green graphic on the left, followed by the company name in blue text. The word "FUJIREBIO" is in a larger, bolder font than "Diagnostics, Inc."

M. Performance Characteristics (if/when applicable):

Both ARCHITECT HE4 and ARCHITECT CA 125 II are previously cleared devices. Analytical performance for ARCHITECT HE4 and ARCHITECT CA 125 II were validated in K093957 and K042731 respectively. There has been no modification of assay methods for ARCHITECT HE4 and ARCHITECT CA 125 II since the original clearance for each assay. Since there have been no modifications of either assay, there is no increased potential for carry-over contamination

Data were generated using the ARCHITECT i2000SR 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) quideline EP5-A2. A panel of five serum samples was tested and evaluated using both premenopausal and postmenopausal forms of the ROMA equation, using three lots of ARCHITECT HE4 Reagent Kits and Calibrators and three lots of ARCHITECT CA 125 II Reagent Kits and Calibrators, 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 for the Combined Data for Premenopausal ROMA Score (N=160 for each panel)

Sample	Mean	Within-Run		Between-Run		Between-Day		Between-Lot		Total
		SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Panel 1	0.6721	0.0459	6.84	0.0152	2.26	0.0204	3.04	0.0269	4.01	0.0590	8.78
Panel 2	1.4404	0.0890	6.18	0.0380	2.64	0.0244	1.69	0.0506	3.51	0.1118	7.76
Panel 3	3.1073	0.1440	4.63	0.0569	1.83	0.0000	0.00	0.1040	3.35	0.1865	6.00
Panel 4	1.1066	0.0679	6.13	0.0153	1.39	0.0154	1.39	0.0531	4.80	0.0889	8.03
Panel 5	8.8753	0.0595	0.67	0.0243	0.27	0.0000	0.00	0.0783	0.88	0.1013	1.14

Summary for the Lot-to-Lot Variability for the Combined Data for Postmenopausal ROMA Score (N=160 for each panel)

Sample	Mean	Within-Run		Between-Run		Between-Day		Between-Lot		Total
		SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Panel 1	1.0614	0.0436	4.10	0.0154	1.45	0.0072	0.68	0.0222	2.09	0.0517	4.88
Panel 2	2.5897	0.0752	2.90	0.0238	0.92	0.0214	0.83	0.0552	2.13	0.0986	3.81
Panel 3	4.9463	0.0911	1.84	0.0295	0.60	0.0154	0.31	0.1341	2.71	0.1655	3.35
Panel 4	2.6272	0.0726	2.76	0.0243	0.92	0.0000	0.00	0.0692	2.63	0.1032	3.93
Panel 5	8.8011	0.0370	0.42	0.0141	0.16	0.0000	0.00	0.0901	1.02	0.0984	1.12

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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 two lots of ARCHITECT HE4 Reagent Kits and two lots of ARCHITECT 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 the Combined Data for Premenopausal ROMA Score (N=120 for each panel)

Sample	Mean	Within-Run		Between-Run		Between-Day		Between-Site		Total
		SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Panel 1	0.6280	0.0368	5.86	0.0222	3.54	0.0227	3.61	0.0408	6.50	0.0635	10.11
Panel 2	1.3702	0.0931	6.80	0.0775	5.65	0.0000	0.00	0.0476	3.47	0.1301	9.50
Panel 3	2.9969	0.1412	4.71	0.0770	2.57	0.0000	0.00	0.0741	2.47	0.1771	5.91
Panel 4	1.0451	0.0612	5.86	0.0170	1.62	0.0264	2.53	0.0293	2.81	0.0748	7.16
Panel 5	8.8501	0.0701	0.79	0.0000	0.00	0.0279	0.32	0.0104	0.12	0.0762	0.86

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

Sample	Mean	Within-Run		Between-Run		Between-Day		Between-Site		Total
		SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
Panel 1	1.0313	0.0349	3.38	0.0246	2.39	0.0110	1.07	0.0407	3.95	0.0600	5.82
Panel 2	2.5296	0.0808	3.20	0.0803	3.18	0.0000	0.00	0.0486	1.92	0.1239	4.90
Panel 3	4.8604	0.0923	1.90	0.0504	1.04	0.0000	0.00	0.0888	1.83	0.1376	2.83
Panel 4	2.5654	0.0705	2.75	0.0000	0.00	0.0243	0.95	0.0572	2.23	0.0940	3.66
Panel 5	8.7739	0.0405	0.46	0.0117	0.13	0.0075	0.09	0.0389	0.44	0.0579	0.66

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

ARCHITECT CA 125 II Calibrator and Controls

The OC125 defined antigen is used in the ARCHITECT CA 125 II Calibrators and Controls. The concentrations are specific to each calibrator and control level. This material is obtained from Fujirebio Diagnostics, Inc. proprietary human ovarian carcinoma cell line, McDonalds. OC 125 defined antigen is produced by the McDonalds cell line. The stock solution for calibrators is prepared by adding OC 125 defined antigen to a diluent to achieve the desired concentrations. The stock solution is tested to determine its actual concentration. Each Calibrator and Control is then prepared based on the actual concentration of the stock solution.

ARCHITECT HE4 Calibrator and Controls

Ig-HE4 is a fusion protein consisting of a human Fc antibody fragment and Human Epididymis protein HE4. The Ig-HE4 antigen is used as a calibrator protein in the HE4 assay to determine HE4 concentrations in human serum samples. The protein is produced in a stably transfected Chinese Hamster Ovary (CHO) cell line. The cell line was adapted to serum free growth medium at Fujirebio Diagnostics, Inc. Recombinant antigen is used to prepare calibrators and controls for ARCHITECT HE4.

Stability

Specimen:

ARCHITECT ROMA is intended for use with serum. The specimen stability and storage claims are limited to the ARCHITECT HE4 assay. Serum can be stored at 2-8°C for 4 days before being tested. Samples can be stored at -10°C or colder for longer periods.

Calibration Curve: For ARCHITECT HE4 and ARCHITECT CA 125 II, the calibration curve is stable up to 30 days.

Reagent Closed-Vial: Users are instructed to refer to the individual stability information in the package insert of each assay. The claimed stability for ARCHITECT HE4 is up to 12 months at 2–8°C. The claimed shelf life for ARCHITECT CA 125 II is 12 months at 2–8°C.

Reagent Open-Vial: Users are instructed to refer to the stability information in the package insert for reagents used in the individual assay. The stability of the opened reagents used in ARCHITECT HE4 and ARCHITECT CA 125 II kit are listed below:

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	Stability
Component	Opened Vial	Opened Vial/On-Board
ARCHITECT CA 125 IIReagent Kit	2-8°C for 12 months	30 days at 2-8°C
ARCHITECT CA 125 IICalibrators	2-8°C for 12 months
ARCHITECT HE4Reagent Kit	2-8°C for 12 months	30 days at 2-8°C
ARCHITECT HE4Calibrators	2-8°C for 12 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 an ARCHITECT 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 ARCHITECT ROMA. The potential interferents listed in the table below were spiked into 3 serum panels (Low, Medium, and High). The samples were assayed, and the ROMA scores of the spiked samples were compared to reference samples.

PotentiallyInterferingSubstance	Concentration	Low b		Medium c		High d
		Pre	Post	Pre	Post	Pre	Post
Hemoglobin a	2 mg/mL	12	5	1	1	6	1
	1 mg/mL	-1	-1	2	0	5	1
Bilirubin(Conjugated)	20 mg/dL	-2	0	-5	-1	-6	-2
Bilirubin(Unconjugated)	20 mg/dL	1	1	-4	-2	-2	0
Protein a	12 g/dL	-7	-5	-11	-7	-11	-4
	10 g/dL	-7	-3	-8	-6	-8	-3

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PotentiallyInterferingSubstance	Concentration	% Interference
		Low b		Medium c		High d
		Pre	Post	Pre	Post	Pre	Post
Triglyceride	3 g/dL	-3	-4	-3	0	0	0
Human Anti-MouseAntibodies (HAMA)	1000 ng/mL	-2	8	-1	2	1	0
Rheumatoid Factor(RF)	500 IU/mL	-2	-2	-3	-1	0	0

ª Samples containing hemoglobin at >1 mg/mL and protein at ≥12 g/dL demonstrated interference.

8 approximately 15 U/mL CA 125 II and 50 pM HE4

& approximately 40 U/mL CA 125 II and 60 pM HE4

ಳ approximately 100 U/mL CA 125 II and 100 pM HE4

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

ARCHITECT ROMA method comparison study was performed using specimens consistent with CLSI guideline EP9-A2-IR using the Deming and Passing-Bablok regression method to compare ARCHITECT ROMA to ROMA (HE4 EIA + ARCHITECT CA 125 II). The data are summarized in the following table.

MenopausalStatus	CorrelationCoefficient(r)	Regression	Intercept	95% CI	Slope	95% CI
Premenopausal	0.983	Deming	-0.097	-0.165 -0.029	0.983	0.939 1.027
		Passing-Bablok	0.005	-0.038 0.029	0.924	0.870 0.996
Postmenopausal	0.999	Deming	-0.041	-0.074 -0.007	0.997	0.988 1.006
		Passing-Bablok	-0.015	-0.044 0.005	0.997	0.987 1.004

b. Matrix Comparison

Serum is the only claimed matrix.

1. Clinical studies:
- a. Clinical sensitivity:

See 3(c) below

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b. Clinical specificity:
See 3(c) below
C. Other clinical supportive data (when a. and b. are not applicable):
Risk of Ovarian Malignancy Algorithm in Patients Presenting with an Adnexal Mass The effectiveness of 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 459 women were evaluated in the study. For each patient, an initial cancer risk assessment was completed, providing an assessment of the patient's mass as benign or malignant. The corresponding histopathology reports were collected after surgery.

The histopathological classifications of the 459 patients (250 premenopausal and 209 postmenopausal) are summarized in the table below.

Histopathological	Total		Premenopausal		Postmenopausal
Classification	N	%	N	%	N	%
Benign Pathology	374	81.5	229	91.6	145	69.4
Low Malignant Potential(LMP) /Borderline	18	3.9	7	2.8	11	5.3
Epithelial Ovarian Cancer(EOC)	48	10.5	9	3.6	39	18.7
Non-EOC	2	0.4	0	0.0	2	1.0
Other Gynecological Cancer	9	2.0	3	1.2	6	2.9
Other Cancer	7	1.5	1	0.4	6	2.9
Metastatic Cancer	1	0.2	1	0.4	0	0.0

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Use of ROMA for stratification into likelihood of finding malignancy on surgery

Using a preoperatively collected serum sample, ARCHITECT ROMA was determined and the patient was stratified into a low or a high likelihood group for finding malignancy on surgery. The stratification of the 459 patients (250 premenopausal and 209 postmenopausal) presenting with an adnexal mass into high likelihood of harboring malignant disease using ARCHITECT ROMA is shown in the table below.

	Total		Premenopausal		Postmenopausal
	N	%	N	%	N	%
All EOC a	45/48	93.8	9/9	100.0	36/39	92.3
EOC Stage I + II	9/12	75.0	3/3	100.0	6/9	66.7
EOC Stage III + IV	34/34	100.0	5/5	100.0	29/29	100.0
LMP Tumors	13/18	72.2	4/7	57.1	9/11	81.8
Other Cancer b	11/19	57.9	2/5	40.0	9/14	64.3
All Cancer and LMP Tumors	69/85	81.2	15/21	71.4	54/64	84.4
a 2 EOC patients were unstagedb non-epithelial ovarian cancer, other gynecologic, and non-gynecologic cancers

The stratification of 422 women, 48 with epithelial ovarian cancer and 374 with benign disease, into low likelihood and high likelihood groups for finding malignancy on surgery using ARCHITECT ROMA is shown in the table below.

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	Premenopausal (N=238)		Postmenopausal (N=184)
	% (N)	95% CIa	% (N)	95% CIa
Sensitivity	100.0 (9/9)	(70.1,99.2)	92.3 (36/39)	(79.7,97.2)
Specificity	86.5 (198/229)	(81.4,90.3)	85.5 (129/145)	(78.9,90.3)
TP - FP b	86.5	(81.9,91.0)	77.8	(67.5,88.2)
PPV c	22.5 (9/40)	(12.3,37.4)	63.2 (36/57)	(50.2,74.4)
NPV d	100.0 (198/198)	(98.1,99.9)	97.6 (124/127)	(93.3,99.2)
Prevalence	3.8 (9/238)		21.2 (39/184)
a Confidence Intervalb True Positive rate - False Positive ratec Positive Predictive Value

° Positive Predictive Value
ª Negative Predictive Value

Negative Predictive Value

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Adjunctive use of ARCHITECT ROMA with ICRA for stratification into low likelihood and high likelihood groups for finding malignancy on surgery

The performance for the adjunctive use of ARCHITECT ROMA with ICRA (ARCHITECT ROMA and/or ICRA being positive for high likelihood of finding malignancy on surgery) was evaluated. Premenopausal and postmenopausal women combined for all cancers.

Malignancy by Pathology a
	Initial Cancer Risk Assessment
	Positive b	Negative c	Total
ARCHITECT ROMA	Positive b	56	12	68
	Negative c	6	11	17
	Total	62	23	85
No Malignancy by Pathology a
		Initial Cancer Risk Assessment
		Positive b	Negative c	Total
ARCHITECT ROMA	Positive b	20	32	52
	Negative c	39	283	322
	Total	59	315	374

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

b High likelihood of finding malignancy on surgery

° Low likelihood of finding malignancy on surgery

Adjunctive use ARCHITECT ROMA with ICRA produced a statistically significant improvement in the negative predictive value (NPV). The NPV for correctly classifying benign patients into the low likelihood group increased from 93.2 to 96.3%, making the adjunctive use of ARCHITECT ROMA with ICRA effective in ruling out malignancy.

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	ICRA		ARCHITECT ROMA		Adjunctive
	%	95% CI a	%	95% CI a	%	95% CI a
Sensitivity	72.9	62.7,81.2	80.0	70.3,87.1	87.1	78.3,92.6
Specificity	84.2	80.2,87.6	86.1	82.2,89.2	75.7	71.1,79.7
PPV b	51.2	42.4,60.0	56.7	47.7,65.2	44.8	37.5,52.5
NPV c	93.2	90.0,95.4	95.0	92.1,96.8	96.3	93.4,97.9
TP - FP d	57.2	46.8,67.5	66.1	56.7,75.5	62.7	54.2,71.3
PLR e	4.624	3.538,6.042	5.754	4.376,7.565	3.578	2.939,4.355
NLR f	0.321	0.226,0.457	0.232	0.152,0.356	0.171	0.098,0.298
Prevalence	18.5%
a Confidence Intervalb Positive Predictive Valuec Negative Predictive Valued True Positive rate - False Positive ratee Positive Likelihood Ratiof

Negative Likelihood Ratio

4. Clinical cut-off:

The following cut-offs are used to interpret the result. The ARCHITECT ROMA score is between 0.0 and 10.0.

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

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5. Expected values/Reference range:

Descriptive Statistics of ARCHITECT ROMA Results for Pre- and Postmenopausal Healthy Subjects:

	Pre- andPostmenopausalHealthy SubjectsCombined	PremenopausalHealthy Subjects	PostmenopausalHealthy Subjects
N	242	122	120
ARCHITECT ROMA Result
Mean (SD)	0.83 (0.56)	0.61 (0.48)	1.05 (0.55)
Median	0.83	0.43	0.92
Range (min, max)	0.11-3.56	0.11-2.88	0.36-3.56
Reference Interval (5th percentile, 95thpercentile)	0.24, 1.98	0.21, 1.65	0.46, 2.02
ARCHITECT ROMA Likelihood (n, %)
High Likelihood	11 (4.5%)	9 (7.4%)	2 (1.7%)
Low Likelihood	231 (95.5%)	113 (92.6%)	118 (93.3%)

Descriptive Statistics of ARCHITECT ROMA Results for Pre- and Postmenopausal (Combined) Benign Subjects

Pre- andPostmenopausalSubjects Combined	BenignGynecologicalDisease	OtherBenignDisease	CHF	Hypertension	Pregnant
N	374	39	40	40	40
ARCHITECT ROMAResult
Mean (SD)	1.13 (1.07)	2.92 (2.48)	2.47 (1.70)	2.07 (1.73)	0.58 (0.24)
Median	0.79	1.73	2.08	1.56	0.54
Range (min, max)	0.10-8.24	0.18-9.44	0.15-7.53	0.50-8.56	0.10-1.05
Reference Interval (5th percentile, 95th percentile)	0.26, 3.01	0.36, 7.94	0.60, 5.09	0.72, 4.75	0.29, 1.01
ARCHITECT ROMALikelihood (n, %)
High Likelihood	52 (13.9%)	17 (43.6%)	14 (35.0%)	10 (25.0%)	0 (0.0%)
Low Likelihood	322 (86.1%)	22 (56.4%)	26 (65.0%)	30 (75.0%)	40 (100.0%)

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Descriptive Statistics of ARCHITECT ROMA Results for Pre- and Postmenopausal (Combined) Cancer Subjects

Pre- andPostmenopausalSubjects Combined	BladderCancer	BreastCancer	EndometrialCancer	GI Cancer	Lung Cancer
N	40	40	40	40	40
ARCHITECT ROMA
Result
Mean (SD)	3.43 (2.48)	2.52 (2.20)	4.19 (3.38)	2.67 (2.00)	3.18 (1.85)
Median	2.67	1.58	2.69	2.05	3.13
Range (min, max)	0.49-9.93	0.25-9.79	0.30-9.95	0.64-9.08	0.51-7.82
Reference Interval (5thpercentile, 95thpercentile)	0.83, 9.16	0.56, 6.86	0.39, 9.58	0.69, 7.26	0.62, 5.93
ARCHITECT ROMA
Likelihood (n, %)
High Likelihood	19 (47.5%)	16 (40.0%)	21 (52.5%)	15 (37.5%)	22 (55.0%)
Low Likelihood	21 (52.5%)	24 (60.0%)	19 (47.5%)	25 (62.5%)	18 (45.0%)

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

N. Proposed Labeling:

The labeling satisfies the requirements of 21 CFR Part 809.10.

O. Conclusion:

The results of these analytical (nonclinical) and clinical studies demonstrate that ARCHITECT 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: