Notification



Notification Issue Date:



Medical Policy Bulletin


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

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



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 and Risk of Ovarian Malignancy Algorithm (ROMA™), the Company has determined that the safety and/or effectiveness of proteomics (protein)-based testing for the evaluation of ovarian (adnexal) masses using OVA1® Test and ROMA™ cannot be established by review of the available published peer-reviewed literature. Therefore, proteomics (protein)--based testing for the evaluation of ovarian (adnexal) masses using OVA1® Test 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

REQUIRED DOCUMENTATION

The Company may conduct reviews and audits of services to our members regardless of the participation status of the provider. Medical record documentation must reflect the medical necessity of the care and services provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

An order for each item billed must be signed and dated by the professional provider who is treating the member and kept on file by the supplier. Medical record documentation must include a shipment confirmation or member's receipt of supplies and equipment. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.
Guidelines

BLACK BOX WARNINGS

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

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 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

OVA1® Test was classified by the FDA on July 16, 2009 as a Class II device and has permission to be marketed as an aid to further assess the likelihood that malignancy is present when the professional provider's independent clinical and radiological evaluation does not indicate malignancy.

ROMA™ was classified by the FDA on September 1, 2011 as a Class II device and has permission to be marketed as an 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.

Description

Ovarian cancer is the leading cause of death from gynecologic cancers in the United States and the fifth-leading cause of cancer deaths among women. It accounts for three percent of all female cancers and is the ninth most common cancer among women. There are an estimated 22,000 new cases annually in the United States. Women who are postmenopausal are at the greatest likelihood for ovarian cancer. Ovarian cancer is recognized as difficult to diagnose because its symptoms are easily confused with other non-cancerous conditions. Three quarters of cases of ovarian cancer are diagnosed at an advanced stage, when it is more difficult to treat. Of individuals who are diagnosed early (Stage I-II), more than 90 percent will live past five years. However, only 25 percent of cases are diagnosed in the early stages.

There are a variety of biomarkers that have been studied in 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. Presently, two tests (OVA1® Test and ROMA™) based on this principle have been cleared by the US Food and Drug Administration (FDA) for use in women with adnexal masses as an aid to further assess the likelihood that malignancy is present. A suggested use of these tests is to identify women who are at increased risk, have a higher likelihood of malignant disease, and may benefit from referral to a gynecologic oncologist for specialist treatment.

OVA1® TEST AND RISK OF OVARIAN MALIGNANCY ALGORITHM (ROMA™)

OVA1® Test is a laboratory test that measures the levels of five proteins (i.e., transthyretin [pre-albumin], apolipoprotein A1, beta-2-microglobulin, transferrin, and the CA-125 cancer antigen) found in the blood and believed to be markers of ovarian cancer, and then uses a proprietary software called OvaCalc®, which contains an algorithm to calculate a single numerical score. The test combines the five separate results into a single numerical score between 0.0 and 10.0 to indicate the likelihood that the pelvic mass is benign or malignant for pre-menopausal and post-menopausal subjects separately. Women who are pre-menopausal have a cut-off of 5.0, whereas postmenopausal women have a 4.4 cut-off, for a likelihood of finding malignancy. A high OVA1® Test score is not a diagnosis of cancer; rather, it indicates an increased risk.

ROMA™ is a qualitative serum test that uses an algorithm that combines the results of two analytes, Human Epididymis protein 4 enzyme immunometric assay (HE4 EIA), and ARCHITECT CA 125 II™ (a chemiluminescent micorparticle immunoassay for the quantitative determination of CA 125), and menopausal status into a numerical score between 0.0 and 10.0, which is calculated using the separate algorithm both manually and by using ROMA Calculator Tool Software. Women who are pre-menopausal have a cut-off of 1.31, whereas postmenopausal women have a cut-off of 2.77, for a likelihood of finding malignancy. ROMA™ is intended to assist in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy upon surgery.

US FOOD AND DRUG ADMINISTRATION (FDA)
On July 16, 2009, the OVA1® Test (Vermillion, Inc. Fremont, CA) was cleared for market by the FDA as a 510(k) submission. No predicate device was identified, and the review decision was based on the de novo 510(k) review process, which allows novel products with moderate- or low-risk profiles and without predicates, which would ordinarily require premarket approval as a class III device, to be down-classified in an expedited manner and brought to market with a special control as a class II device. According to the product labeling, the OVA1® Test should not be used without an independent clinical and radiological evaluation and is not intended to be a screening test or to determine whether an individual should proceed to surgery. Off-label use of the OVA1® Test carries the risk of a high frequency of unnecessary further testing and surgery due to false positive results, and/or delayed tumor diagnosis due to false negative results.

On September 01, 2011 the ROMA™ test (Fujirebio Diagnostics, Inc., Malvern, PA) was cleared by the FDA as a 510(k) submission. The predicate device for ROMA™ is the OVA1® Test, and includes the same FDA indications as the OVA1® Test. 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 or to determine whether an individual should proceed to surgery. Incorrect use of the ROMA™ test also carries the risk of unnecessary further testing, surgery, and/or delayed diagnosis.

Technical Performance

Evidence on the technical performance of these tests has been evaluated by the U.S. Food and Drug Administration (FDA) and is available through the FDA website. This information generally indicates acceptable technical performance for use in clinical care.

Diagnostic Performance

Use of the OVA1® Test and ROMA™ proteomic tests in combination with clinical assessment appears to produce very modest changes in diagnostic performance for identifying adnexal masses negative for ovarian cancer. Both tests when added to pre-testing clinical assessment produced a fall in the positive predictive value of diagnosis with a small increase in the negative predictive value. The changes observed in the negative predictive value were of uncertain statistical and clinical significance.

Evidence Related to Improvement of Clinical Outcomes (Clinical Utility)

No outcome studies have been performed using the OVA1® Test or ROMA™. It is not clear what impact use of either test would have on long-term healthcare outcomes. As is the case for false-positive cases identified and referred using existing clinical and radiologic diagnostic criteria, there is no evidence of harm to individuals identified as false-positives.

The use of genomic testing to triage individuals for malignancy may be only one of many factors in decision making about where treatment should be delivered (i.e., referral patterns). The clinical significance of the addition of these tests to currently used diagnostic modalities is unknown.

Evidence suggests that for individuals who are considering treatment by a non-gynecologic oncologist (e.g., gynecologists, primary care physicians), use of proteomic tests will decrease the likelihood that an adnexal mass is categorized as benign when it is actually malignant. This might impact referral patterns to a gynecologic oncologist and decrease the likelihood that an individual will require a second follow-up procedure for comprehensive staging, lymphadenectomy, and/or tumor debulking, but empirical evidence of this is lacking. Because of the unknown effect on referral patterns, the effect on health outcomes is uncertain.

Although the OVA1® Test and ROMA™ have both been analytically validated, and clinical performances of these tests have been reported in prospective multi-center clinical trials;changes in the observed sensitivity and negative predictive value of testing has been small and of uncertain diagnostic value. No studies have been performed that directly evaluate the impact on referral patterns, and no studies have evaluated the impact on health outcomes. Since the performance of the original trials in preparation for FDA submissions, neither test has had an evaluation of performance independently confirmed by independent investigators. Furthermore, there is a lack of agreement regarding the defined clinical role(s) of these tests among the American Congress of Obstetricians and Gynecologists (ACOG), National Comprehensive Cancer Network (NCCN), The National Cancer Institute (NCI), National Institute for Health and Care Excellence (NICE), U.S. Preventive Services Task Force (USPSTF) Recommendations, and The Society for Gynecologic Oncology (SGO).

SUMMARY

A variety of gene-based biomarkers have been studied in 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. Two tests based on this principle (OVA1™ test, ROMA™ test) have been cleared by the U.S. Food and Drug Administration for use in women with adnexal masses undergoing surgery as an aid to further assess the likelihood that malignancy is present.

The evidence for use of proteomics-based testing (OVA1 test or ROMA test) in conjunction with clinical assessment in patients who have adnexal masses undergoing surgery includes studies assessing the technical performance and diagnostic accuracy of the tests. Relevant outcomes are overall survival and test accuracy. OVA1 is intended to be used in patients for whom clinical assessment does not indicate cancer. When used with clinical assessment in this manner, sensitivity for ovarian malignancy was 92% and specificity was 42%. ROMA is intended to be used in conjunction 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%. It is uncertain whether these test characteristics result in meaningful benefit to patients. The chain of evidence supporting improved outcomes resulting from improved diagnostic test performance is weak. There is no direct evidence in terms of assessing patient outcomes based on the use of such testing prior to undergoing surgery. The evidence is insufficient to determine the effects of the technology on health outcomes.

The evidence for use of proteomics-based testing (OVA1 test or ROMA test) in patients who have other clinical situations involving ovarian cancer (e.g., screening, selection for surgery, posttreatment cancer monitoring) is lacking. Relevant outcomes are overall survival and test accuracy. The evidence is insufficient to determine the effects of the technology on health outcomes.
References


Alcazar JL, Rodriguez D. Three-dimensional power doppler vascular sonographic sampling for predicting ovarian cancer in cystic-solid and solid vascularized masses. J Ultrasound Med. 2009; 28(3):275-281.

American Cancer Society. Ovarian Cancer. [American Cancer Society Web site]. 2013. Available at:http://www.cancer.org/cancer/ovariancancer/index. Accessed June 01st, 2016.

American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Committee Opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer. Obstet Gynecol. 2011;117(3):742-746.

American Congress of Obstetricians and Gynecologists (ACOG). Committee Opinion: number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol. 2002; 100(6):1413-1416.

Andersen MR, Goff BA, Lowe KA, et al. Use of a Symptom Index, CA125, and HE4 to predict ovarian cancer. Gynecol Oncol. 2010;116(3):378-383.

Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Multi-analyte testing for the evaluation of adnexal masses. TEC Assessments 2012; Volume 27, tab TBA.

Bristow RE, Zahurak ML, Diaz-Montes TP, et al. Impact of surgeon and hospital ovarian cancer surgical case volume on in-hospital mortality and related short-term outcomes. Gynecol Oncol. 2009;115(3):334-338.

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. 2009;112(2):422-436.

Fujirebio Diagnostics Inc. (FDI). Roma. Instructions for use. [FDI Web site]. September 2011. Available at: http://www.fdi.com/documents/products/inserts/eia/ROMA%20HE4%20EIA%20404-10US.%202011-09.%20F5064%20r0.pdf. Accessed June 01st, 2016.

Fung ET. A recipe for proteomics diagnostic test development: the OVA1 test, from biomarker discovery to FDA clearance. Clin Chem. 2010;56(2):327-329.

Giede KC, Kieser K, Dodge J, et al. Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol. 2005;99(2):447-461.

Goff BA, Matthews BJ, Larson EH, et al. Predictors of comprehensive surgical treatment in patients with ovarian cancer. Cancer. 2007;109(10):2031-2042.

Grabowski JP, Harter P, Buhrmann C, et al. Re-operation outcome in patients referred to a gynecologic oncology center with presumed ovarian cancer FIGO I-IIIA after sub-standard initial surgery. Surg Oncol. 2012;21(1):31-35.

Hoskins W, Rice L, Rubin S. Ovarian cancer surgical practice guidelines. Society of Surgical Oncology practice guidelines. Oncology. (Williston Park) 1997;11(6):896-900, 03-4.

Medical Devices: Ovarian adnexal mass assessment score test system; Labeling; Black box restrictions. 21 CFR Part 866, Federal Register 2011;76(251):82128-82123.

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. 2008; 108(2):402-408.

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. 2011;118(2 Pt 1):280-288.

Muller CY. Doctor, should I get this new ovarian cancer test-OVA1? Obstet Gynecol. 2010; 116(2 Pt 1):246-247.

National Cancer Institute (NCI). PDQ genetics of breast and ovarian cancer. [NCI Web site]. 09/04/2013. Available at: http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessionalAccessed June 01st, 2016.

National Comprehensive Cancer Network (NCCN). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. NCCN Clinical Practice Guidelines in Oncology. [NCCN Web site]. February 2013. Available at: http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf [via subscription only]. Accessed June 01st, 2016.

National Institute for Health and Clinical Excellence (NICE). The recognition and initial management of ovarian cancer. Clinical Guideline 122. [NICE Web site]. April 2011.

Novitas Solutions, Inc. Local Coverage Determination (LCD). L33142: Biomarkers for Oncology. [Novitas Solutions Web site]. Original: 08/01/13. Available at: https://www.novitas-solutions.com/policy/mac-ab/l33142-r1.html. Accessed June 01st, 2016.

OVA1. OVA1® is the first FDA-cleared blood test that helps evaluate an ovarian mass for malignancy prior to planned surgery. [OVA1 Web site]. 2013. Available at: http://ova-1.com/. Accessed June 01st, 2016.

Partheen K, Kristjansdottir B, Sundfeldt K. Evaluation of ovarian cancer biomarkers HE4 and CA-125 in women presenting with a suspicious cystic ovarian mass. J Gynecol Oncol. 2011; 22(4):244-252.

Quest Diagnostics. US Food and Drug Administration clears Vermillion's OVA1(TM) test to determine likelihood of ovarian cancer in women with pelvic mass. [Quest Diagnostics Web site]. 2011. Available at: http://ir.questdiagnostics.com/phoenix.zhtml?c=82068&p=irol-newsArticle&id=1331027. Accessed June 01st, 2016.

Society of Gynecologic Oncologists (SGO). Statement regarding OVA1. [SGO Web site]. September 2009.

Tingulstad S, Skjeldestad FE, Hagen B. The effect of centralization of primary surgery on survival in ovarian cancer patients. Obstet Gynecol. 2003;102(3):499-505.

US Food and Drug Administration (FDA). Center for Devices and Radiological Health. OVA1™ Test. Premarket approval letter. [FDA Web site]. 09/11/09. Available at:
http://www.accessdata.fda.gov/cdrh_docs/pdf8/K081754.pdf. Accessed June 01st, 2016.

US Food and Drug Administration. 510(k) Substantial Equivalence Determination Decision Summary: OVA1™ Test (K081754). [FDA Web site]. 07/16/09. Available at: http://www.accessdata.fda.gov/cdrh_docs/reviews/K081754.pdf. Accessed June 01st, 2016.

US Food and Drug Administration. 510(k) Substantial Equivalence Determination Decision Summary: ROMA™ Test (K103358). [FDA Web site]. 09/01/11. Available at: http://www.accessdata.fda.gov/cdrh_docs/reviews/K103358.pdf. Accessed June 01st, 2016.

U.S. Preventive Services Task Force. Screening for Ovarian Cancer. 2012; http://www.uspreventiveservicestaskforce.org/uspstf12/ovarian/ovarcancerrs.htm. Accessed June 01st, 2016.

Van Gorp T, Cadron I, Despierre E, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Br J Cancer. 2011;104(5):863-870.

Van Gorp T, Veldman J, Van Calster B, et al. Subjective assessment by ultrasound is superior to the risk of malignancy index (RMI) or the risk of ovarian malignancy algorithm (ROMA) in discriminating benign from malignant adnexal masses. Eur J Cancer. 2012;48(11):1649-1656.

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. 2010;36(1):81-87.

Vernooij F, Heintz P, Witteveen E, et al. The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review. Gynecol Oncol. 2007;105(3):801-812.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

0003U, 81500, 81503


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


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

Coding and Billing Requirements


Cross References


Policy History

06.02.43b
11/21/2018This policy has been reissued in accordance with the Company's annual review process.
11/22/2017This policy has been reissued in accordance with the Company's annual review process.


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


Version Effective Date: 02/01/2017
Version Issued Date: 02/01/2017
Version Reissued Date: 11/27/2018

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Independence Blue Cross is an independent licensee of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.