Commercial

Medical Policy

Title:

Proteomic (Protein)-Based Testing for the Evaluation of Ovarian (Adnexal) Masses Using OVA1® Test and Risk of Ovarian Malignancy Algorithm (ROMA™)

Policy #:

06.02.43b

Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

EXPERIMENTAL/INVESTIGATIONAL

For individuals enrolled in the Company's commercial products, although the US Food and Drug Administration (FDA) has approved OVA1® Test, Overa™ (also referred as next-generation OVA1®), and Risk of Ovarian Malignancy Algorithm (ROMA™), the Company has determined that the safety and/or effectiveness of proteomics (protein)-based testing/multimarker serum testing for the evaluation of ovarian (adnexal) masses using OVA1® Test, Overa™ (also referred as next-generation OVA1®), and ROMA™ cannot be established by review of the available published peer-reviewed literature. Therefore, proteomics (protein)--based testing/multimarker serum testing for the evaluation of ovarian (adnexal) masses using OVA1® Test, Overa™ (also referred as next-generation OVA1®), and ROMA™ are considered experimental/investigational by the Company and not covered, including but not limited to the following:

Preoperative evaluation of adnexal masses to triage for malignancy
Screening for ovarian cancer
Selection of individuals for surgery for an adnexal mass
Evaluation of individuals with clinical and radiologic evidence of malignancy
Evaluation of individuals with nonspecific signs or symptoms suggesting possible malignancy
Postoperative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment

Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

In December 2011, the FDA amended its regulation for classifying ovarian adnexal mass assessment score test systems. The change required that off-label risks be highlighted using a black box warning. The warning is intended to mitigate the risk to health associated with off-label use as a screening test, stand-alone diagnostic test, or as a test to determine whether to proceed with surgery. Considering the history and currently unmet medical needs for ovarian cancer testing, the FDA concluded that there is a risk of off-label use of this device. To address this risk, the FDA requires that manufacturers provide notice concerning the risks of off-label uses in the labeling, advertising, and promotional material of ovarian adnexal mass assessment score test systems. Manufacturers must address the following risks:

Women without adnexal pelvic masses (i.e., for cancer "screening") are not part of the intended use population for the ovarian adnexal mass assessment score test systems. Public health risks associated with false-positive results for ovarian cancer screening tests are well described in the medical literature and include morbidity or mortality associated with unneeded testing and surgery. The risk from false-negative screening results also includes morbidity and mortality due to failure to detect and treat ovarian malignancy.
Analogous risks, adjusted for prevalence and types of disease, arise if test results are used to determine the need for surgery in patients who are known to have ovarian adnexal masses.
If used outside the "OR" rule that is described in this special control guidance, results from ovarian adnexal mass assessment score test systems pose a risk for morbidity and mortality due to nonreferral for oncologic evaluation and treatment.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, proteomic (protein)--based testing for the evaluation of ovarian (adnexal) masses using OVA1® Test, Overa™ (also referred as next-generation OVA1®), and Risk of Ovarian Malignancy Algorithm (ROMA™) is not eligible for payment under the medical benefits of the Company’s products because this service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

In July 2009, the OVA1® test (Aspira Labs [Austin, TX]) was cleared for marketing by the FDA through the 510(k) process. OVA1® was designed as a tool to further assess the likelihood that malignancy is present when the physician's independent clinical and radiologic evaluation does not indicate malignancy.

In September 2011, the Risk of Ovarian Malignancy Algorithm (ROMA™ test; Fujirebio Diagnostics [Sequin, TX]) was cleared for marketing by the FDA through the 510(k) process. The intended use of ROMA™ is as an aid, in conjunction with clinical assessment, in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at a high or low likelihood of finding malignancy on surgery.

In March 2016, a second-generation test called Overa™ (also referred as next-generation OVA1®), in which 2 of the 5 biomarkers in OVA1® are replaced with human epididymis secretory protein 4 and follicle-stimulating hormone, was cleared for marketing by the FDA through the 510(k) process. Similar to OVA1®, Overa™ generates a low- or high-risk of malignancy on a scale from 0 to 10.

Description

A variety of serum biomarkers have been studied for their association with ovarian cancer. Of particular interest have been tests that integrate results from multiple analytes into a risk score to predict the presence of disease. Three tests based on this principle, OVA1, Overa (the second-generation OVA1 test), and the Risk of Ovarian Malignancy Algorithm (ROMA) have been cleared by the U.S. Food and Drug Administration. The intended use of OVA1 and Overa is as an aid to further assess whether malignancy is present even when the physician's independent clinical and radiologic evaluation does not indicate malignancy. The intended use of ROMA is as an aid, in conjunction with clinical assessment, to assess whether a premenopausal or a postmenopausal woman who presents with an ovarian adnexal mass is at a high or low likelihood of finding malignancy on surgery.

For individuals who have adnexal mass(es) undergoing surgery for possible ovarian cancer who receive multimarker serum testing with clinical assessment preoperatively to assess ovarian cancer risk, the evidence includes studies assessing the technical performance and diagnostic accuracy. Relevant outcomes are overall survival and test accuracy. OVA1 and Overa are intended for use in patients for whom clinical assessment does not indicate cancer. When used in this manner, sensitivity for ovarian malignancy was 92% and specificity was 42% with OVA1; with Overa, sensitivity was 94% and specificity was 65%. ROMA is intended for use with clinical assessment, but no specific method has been defined. One study, which used clinical assessment and ROMA results, showed a sensitivity of 90% and specificity of 67%. However, the National Comprehensive Cancer Network guidelines recommend (category 1) that all patients undergoing surgery should undergo surgery by an experienced gynecologic oncologist. Given the National Comprehensive Cancer Network recommendation, direct evidence will be required to demonstrate that the use of U.S. Food and Drug Administration (FDA) cleared multimarker serum testing to inform decisions regarding referral to a gynecologic oncology specialist for surgery has clinical usefulness. Direct evidence of clinical usefulness is provided by studies that have compared health outcomes for patients managed with and without the FDA cleared multimarker serum testing. Because these are intervention studies, the preferred evidence would be from randomized controlled trials. No trials were identified that have evaluated whether referral based on FDA cleared multimarker serum testing improves health outcomes.

References

Al Musalhi K, Al Kindi M, Al Aisary F, et al. Evaluation of HE4, CA-125, Risk of Ovarian Malignancy Algorithm (ROMA) and Risk of Malignancy Index (RMI) in the Preoperative Assessment of Patients with Adnexal Mass. Oman Med J. Sep 2016; 31(5): 336-44.

Bristow RE, Smith A, Zhang Z, et al. Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay. Gynecol Oncol. Feb 2013; 128(2): 252-9.

Chacon E, Dasi J, Caballero C, et al. Risk of Ovarian Malignancy Algorithm versus Risk Malignancy Index-I for Preoperative Assessment of Adnexal Masses: A Systematic Review and Meta-Analysis. Gynecol Obstet Invest. 2019; 84(6): 591-598.

Cho HY, Park SH, Park YH, et al. Comparison of HE4, CA125, and Risk of Ovarian Malignancy Algorithm in the Prediction of Ovarian Cancer in Korean Women. J Korean Med Sci. Dec 2015; 30(12): 1777-83.

Dayyani F, Uhlig S, Colson B, et al. Diagnostic Performance of Risk of Ovarian Malignancy Algorithm Against CA125 and HE4 in Connection With Ovarian Cancer: A Meta-analysis. Int J Gynecol Cancer. Nov 2016; 26(9): 1586-1593.

du Bois A, Rochon J, Pfisterer J, et al. Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review. Gynecol Oncol. Feb 2009; 112(2): 422-36.

Dunton C, Bullock RG, Fritsche H. Multivariate Index Assay Is Superior to CA125 and HE4 Testing in Detection of Ovarian Malignancy in African-American Women. Biomark Cancer. 2019; 11: 1179299X19853785.

Eskander R, Berman M, Keder L. Practice Bulletin No. 174: Evaluation and Management of Adnexal Masses. Obstet Gynecol. Nov 2016; 128(5): e210-e226.

Fung ET. A recipe for proteomics diagnostic test development: the OVA1 test, from biomarker discovery to FDA clearance. Clin Chem. Feb 2010; 56(2): 327-9.

Grenache DG, Heichman KA, Werner TL, et al. Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass. Clin Chim Acta. Jan 01 2015; 438: 358-63.

Grossman DC, Curry SJ, Owens DK, et al. Screening for Ovarian Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. Feb 13 2018; 319(6): 588-594.

Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Ovarian Adnexal Mass Assessment Score Test System. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/class-ii-special-controls-guidance-document-ovarian-adnexal-mass-assessment-score-test-system. Updated February 27, 2018. Accessed October 29, 2020.

Han KH, Park NH, Kim JJ, et al. The power of the Risk of Ovarian Malignancy Algorithm considering menopausal status: a comparison with CA 125 and HE4. J Gynecol Oncol. Nov 2019; 30(6): e83.

Matteson KA, Gunderson C, Richardson DL. Committee Opinion No. 716: The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer in Women at Average Risk. Obstet Gynecol. Sep 2017; 130(3): e146-e149.

Moore RG, Brown AK, Miller MC, et al. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol. Feb 2008; 108(2): 402-8.

Moore RG, Hawkins DM, Miller MC, et al. Combining clinical assessment and the Risk of Ovarian Malignancy Algorithm for the prediction of ovarian cancer. Gynecol Oncol. Dec 2014; 135(3): 547-51.

Moore RG, Miller MC, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. Aug 2011; 118(2 Pt 1): 280-8.

National Center for Clinical Excellence (NICE). Ovarian cancer: recognition and initial management [CG122]. 2011; https://www.nice.org.uk/guidance/cg122. Accessed October 28, 2020.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tub Cancer and Primary Peritoneal Cancer. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf Accessed October 29, 2020.

Shen Y, Zhao L, Lu S. Diagnostic performance of HE4 and ROMA among Chinese women. Clin Chim Acta. Jan 2020; 500: 42-46.

Shin KH, Kim HH, Kwon BS, et al. Clinical Usefulness of Cancer Antigen (CA) 125, Human Epididymis 4, and CA72-4 Levels and Risk of Ovarian Malignancy Algorithm Values for Diagnosing Ovarian Tumors in Korean Patients With and Without Endometriosis. Ann Lab Med. Jan 2020; 40(1): 40-47.

Simmons AR, Clarke CH, Badgwell DB, et al. Validation of a Biomarker Panel and Longitudinal Biomarker Performance for Early Detection of Ovarian Cancer. Int J Gynecol Cancer. Jul 2016; 26(6): 1070-7.

Surveillance Epidemology and End Results (SEER) Program. SEER Stat Fact Sheets: Ovarian Cancer. n.d.; https://seer.cancer.gov/statfacts/html/ovary.html. Accessed October 29, 2020.

Terlikowska KM, Dobrzycka B, Witkowska AM, et al. Preoperative HE4, CA125 and ROMA in the differential diagnosis of benign and malignant adnexal masses. J Ovarian Res. Jul 19 2016; 9(1): 43.

U.S. Food and Drug Administration (FDA). 510(k) Substantial Equivalence Determination Decision Summary: OVA1TM Test (K081754) n.d.; https://www.accessdata.fda.gov/cdrh_docs/reviews/K081754.pdf. Accessed October 31, 2020.

U.S. Food and Drug Administration (FDA). 510(k) Substantial Equivalence Determination Decision Summary: OVA1TM Next Generation Test (K150588). n.d.; https://www.accessdata.fda.gov/cdrh_docs/reviews/K150588.pdf. Accessed October 30, 2020.

Van Holsbeke C, Van Belle V, Leone FP, et al. Prospective external validation of the 'ovarian crescent sign' as a single ultrasound parameter to distinguish between benign and malignant adnexal pathology. Ultrasound Obstet Gynecol. Jul 2010; 36(1): 81-7.

Wang J, Gao J, Yao H, et al. Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour Biol. Jun 2014; 35(6): 6127-38.

Yanaranop M, Tiyayon J, Siricharoenthai S, et al. Rajavithi-ovarian cancer predictive score (R-OPS): A new scoring system for predicting ovarian malignancy in women presenting with a pelvic mass. Gynecol Oncol. Jun 2016; 141(3): 479-484.

Coding

CPT Procedure Code Number(s)

0003U, 81500, 81503

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

This service is experimental/investigational for all diagnoses.

HCPCS Level II Code Number(s)

N/A

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 06.02.43b:

09/03/2025	This policy has been reissued in accordance with the Company's annual review process.
04/17/2024	This policy has been reissued in accordance with the Company's annual review process.
02/21/2024	This policy has been reissued in accordance with the Company's annual review process.
05/31/2023	This policy has been reissued in accordance with the Company's annual review process.
06/29/2022	This policy has been reissued in accordance with the Company's annual review process.
11/03/2021	This policy has been reissued in accordance with the Company's annual review process.
12/16/2020	This policy has been reissued in accordance with the Company's annual review process.
11/06/2019	This policy has been reissued in accordance with the Company's annual review process.
11/21/2018	This policy has been reissued in accordance with the Company's annual review process.
11/22/2017	This policy has been reissued in accordance with the Company's annual review process.
02/01/2017	This version of the policy will become effective on 02/01/2017. This policy has been identified for the CPT code update, effective 02/01/2017. The following CPT code has been added to this policy: 0003U

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

2/1/2017

Version Issued Date: