Latest Review Date: November 2023

Category: Laboratory

POLICY:

The use of proteomic testing, including but not limited to the VeriStrat® assay, is considered investigational for all uses in the management of non-small cell lung cancer.

DESCRIPTION OF PROCEDURE OR SERVICE:

Proteomic testing has been proposed as a way to predict survival outcomes, as well as the response to and selection of targeted therapy for patients with non-small-cell lung cancer (NSCLC). One commercially available test (the VeriStrat assay) has been investigated as a predictive marker for response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

Non-Small-Cell Lung Cancer

Lung cancer is the leading cause of cancer death in the United States, with an estimated 228,820 new cases and 135,720 deaths due to the disease in 2020. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and includes nonsquamous carcinoma (adenocarcinoma, large cell carcinoma, other cell types) and squamous cell carcinoma.

Diagnosis

The stage at which lung cancer is diagnosed has the greatest impact on prognosis. Localized disease confined to the primary site has a 59.8% relative five-year survival but accounts for only 18% of lung cancer cases at diagnosis. Mortality increases sharply with advancing stage. Metastatic lung cancer has a relative 5-year survival of 6.3%. Overall, advanced disease, defined as regional involvement and metastatic, accounts for approximately 80% of cases of lung cancer at diagnosis. These statistics are mirrored for the population of NSCLC, with 85% of cases presenting as advanced disease and up to 40% of patients with metastatic disease.

In addition to tumor stage; age, sex, and performance status are independent prognostic factors for survival particularly in early-stage disease. Wheatley-Price et al (2010) reported on a retrospective pooled analysis of 2,349 advanced NSCLC patients from five randomized chemotherapy trials. Women had a higher response rate to platinum-based chemotherapy than men. Greater overall survival (OS) than men were among those with adenocarcinoma histology. A small survival advantage exists for squamous cell carcinoma over non-bronchiolar nonsquamous histology.

The oncology clinical care and research community uses standard measures of performance status: Eastern Cooperative Oncology Group scale and Karnofsky Performance Scale.

Treatment

Treatment approaches are multimodal and generally include surgery, radiotherapy, and chemotherapy (either alone or in combination with another treatment, depending on disease stage and tumor characteristics). Per the National Comprehensive Cancer Network (NCCN) guidelines, the clinical management pathway for stage I or II NSCLC is dependent on surgical findings and may involve resection, radiotherapy, chemotherapy, or chemoradiation. First-line chemotherapy regimens for neoadjuvant and adjuvant therapy utilize platinum-based agents (e.g., cisplatin, carboplatin) in combination with other chemotherapeutics and/or radiotherapy. Treatment recommendations are based on the overall health or performance status of the patient, presence or absence of metastases, as well as the presence or absence of a treatment-sensitizing genetic variant. These aspects inform the selection of targeted and systemic therapies.

For patients who experience disease progression following initial systemic therapy, subsequent treatment regimens are recommended, mainly featuring novel programmed death-ligand 1 (PD-L1) inhibitors. The NCCN also includes recommendations for targeted therapy or immunotherapy in patients with biomarkers, including sensitizing epidermal growth factor receptor (EGFR) mutations. For patients with sensitizing EGFR mutations, recommendations include first-line therapy with EGFR tyrosine kinase inhibitors (TKIs) afatinib, erlotinib, dacomitinib, gefitinib, erlotinib plus ramucirumab, erlotinib plus bevacizumab (nonsquamous), or osimertinib and subsequent therapy with osimertinib. The NCCN does not make any recommendations for the use of EGFR TKIs in the absence of a confirmed sensitizing EGFR mutation. Initial systemic therapy recommendations can be considered for multiple, symptomatic, systemic lesions.

Genomic Alterations

Several common genetic alterations in NSCLC have been targets for drug therapy, the most well-established of which are tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) and crizotinib targeting the anaplastic lymphoma kinase (ALK) gene rearrangement.

EGFR Variants

EGFR, a tyrosine kinase (TK) receptor, is frequently overexpressed and activated in NSCLC. Drugs that inhibit EGFR-signaling either prevent ligand-binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small molecule TKIs). These targeted therapies dampen signal transduction through pathways downstream to the EGFR, such as the RAS/RAF/MAPK cascade. RAS proteins are G proteins that cycle between active and inactive forms in response to stimulation from cell surface receptors such as EGFR, acting as binary switches between cell surface EGFR and downstream signaling pathways. These pathways are important in cancer cell proliferation, invasion, metastasis, and the stimulation of neovascularization.

Variants in 2 regions of the EGFR gene, including small deletions in exon 19 and a point mutation in exon 21 (L858R), appear to predict tumor response to TKIs such as erlotinib. The prevalence of EGFR variants in NSCLC varies by population, with the highest prevalence in nonsmoking Asian women with adenocarcinoma; for that subpopulation, EGFR variants have been reported to as high as 30% to 50%. The reported prevalence of EGFR variants in lung adenocarcinoma patients in the U. S. is approximately 15%.

ALK Variants

In 2% to 7% of NSCLC patients in the US, tumors express a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase gene (EML4-ALK) which is created by an inversion on chromosome 2p. The EML4 fusion leads to ligand-independent activation of ALK, which encodes a receptor TK whose precise cellular function is not completely understood. EML4-ALK variants are more common in never-smokers or light smokers, tend to be associated with younger age of NSCLC onset, and typically do not occur in conjunction with EGFR variants.

Testing for the EML4-ALK fusion gene in patients with adenocarcinoma-type NSCLC is used to predict response to the small molecule TKI crizotinib.

Other Genetic Variants

There are other genetic variants identified in subsets of patients with NSCLC. The role of testing for these variants is to help select targeted therapies for NSCLC.

Targeted Treatment Options

EGFR-Selective Small Molecule Tyrosine Kinase Inhibitors

Orally administered EGFR-selective small-molecule TKIs approved by the U.S. Food and Drug Administration (FDA) for treating NSCLC include gefitinib, erlotinib, afatinib, dacomitinib, mobocertinib, and osimertinib. Although the Food and Drug Administration (FDA) approved gefitinib in 2004, a phase three trial has suggested gefitinib was not associated with a survival benefit. In 2003, the FDA revised gefitinib labeling, further limiting its use to patients who had previously benefited or were currently benefiting from the drug; no new patients were to be given gefitinib. However, in 2015, the FDA approved gefitinib as a first-line treatment for patients with metastatic, sensitizing EGFR-variant positive NSCLC.

In 2015, osimertinib (Tagrisso), an irreversible selective EGFR inhibitor that targets T790M variant-positive NSCLC, received the FDA approval for patients with T890M-variant-positive NSCLC who have progressed on an EGFR TKI.

A meta-analysis by Lee et al (2013) assessing 23 trials on the use of erlotinib, gefitinib, and afatinib in patients with advanced NSCLC reported improved progression-free survival (PFS) in EGFR variant-positive patients treated with EGFR TKIs in the first- and second-line settings and as maintenance therapy. Comparators were chemotherapy, chemotherapy and placebo, and placebo in the first-line, second-line, and maintenance therapy settings. Among EGFR variant-negative patients, PFS was improved with EGFR TKIs compared with placebo for maintenance therapy but not in the first- and second-line settings. OS did not differ between treatment groups in either variant-positive or variant-negative patients. Statistical heterogeneity was not reported for any outcomes. Reviewers concluded that EGFR-variant testing is indicated to guide treatment selection in NSCLC patients.

On the basis of the results of 5 phase 3 randomized controlled trials, the American Society of Clinical Oncology recommended in 2011 that patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for variants to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy.

The primary target population for TKIs in NSCLC is for EGFR variant-positive patients with advanced NSCLC. The use of TKIs in NSCLC for patients with non-sensitizing, wild-type EGFR-variant status is controversial. The TITAN trial (2012) demonstrated no significant differences in OS between erlotinib and chemotherapy as a second-line treatment for patients unselected on the basis of EGFR variant status, with fewer serious adverse events in erlotinib-treated patients. Karampeazis et al (2013) reported similar efficacy between erlotinib and standard chemotherapy (pemetrexed) for second-line therapy in patients unselected on the basis of EGFR variant status. By contrast, in the TAILOR trial (2013), standard chemotherapy was associated with longer OS than erlotinib for second-line therapy in patients with wild-type EGFR. Auliac et al (2014) compared sequential erlotinib plus docetaxel with docetaxel alone as second-line therapy among patients with advanced NSCLC and EGFR wild-type or unknown status. Based on a Simon’s optimal two-stage design, the erlotinib plus-docetaxel strategy was rejected. Despite the rejection, it is worth nothing that in the erlotinib plus docetaxel arm 18 of the 73 patients achieved PFS at 15 weeks; comparatively, in the docetaxel arm, 17 of 74 patients achieved PFS at 15 weeks.

Cicenas et al (2016) reported results of the IUNO randomized controlled trial, which compared maintenance therapy with erlotinib followed by second line chemotherapy if progression occurred to placebo followed by erlotinib if progression occurred in 643 patients with advanced NSCLC with no known EGFR variant. Because there were no significant differences between groups in terms of PFS, objective response rate, or disease control rate; maintenance therapy with erlotinib in patients without EGFR variants was not considered efficacious.

Exon 19 deletions and p.L858R point mutations in exon 21 are the most commonly described sensitizing EGFR mutations, or mutations in EGFR that are associated with responsiveness to EGFR TKI therapy. According to the NCCN, most recent data indicate that NSCLC tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI in any line of therapy.

Proteomics Testing in Selecting Targeted Treatment for Non-Small Cell Lung Cancer

The term proteome refers to the entire complement of proteins produced by an organism, or cellular system and proteomics refers to the large-scale comprehensive study of a specific proteome. The proteome may differ from cell to cell and may vary over time and in response to selected stressors.

A cancer cell’s proteome is related to its genome and genomic alterations. The proteome may be measured by mass spectrometry (MS) or protein microarray. For cancer, proteomic signatures in the tumor or bodily fluids (i.e., pleural fluid or blood) other than the tumor have been investigated as a biomarker for cancer activity.

A commercially available serum-based test (VeriStrat) has been developed and proposed to be used as a prognostic tool to predict expected survival for standard therapies used in the treatment of NSCLC. The test uses matrix-assisted laser desorption ionization MS analysis, and a classification algorithm was developed on a training set of pretreatment sera from three cohorts (Italian A, Japan A, Japan B) totaling 139 patients with advanced NSCLC who were treated with second-line gefitinib. The classification result is either “good” or “poor. Two validation studies using pretreatment sera from two cohorts of patients (Italian B, Eastern Cooperative Oncology Group 3503) totaling 163 patients have been reported.

This assay uses an 8-peak proteomic signature; 4 of the 8 have been identified as fragments of serum amyloid A protein 1. This protein has been found to be elevated in individuals with a variety of conditions associated with acute and chronic inflammation. The specificity for malignant biologic processes and conditions has not been determined. With industry support, Fidler et al (2018) used convenience biorepository samples to investigate 102 analytes for potential correlations between the specific peptide and protein biomarkers and VeriStrat classification. The VeriStrat test is currently marketed as a tool to measure a patient's "immune response to lung cancer." Biodesix indicates that a VeriStrat "Good" result indicates "a disease state that is more likely to respond to standard of care treatment," whereas a VeriStrat "Poor" rating indicates a chronic inflammatory disease state associated with aggressive cancer and patients that "may benefit from an alternative treatment strategy."

Although the VeriStrat® matrix-assisted laser desorption ionization (MALDI)-MS-based predictive algorithm has the largest body of literature associated with it, other investigators have used alternative mass spectrometry methods, such as surface-enhanced laser desorption ionization/time-of-flight mass spectrometry, and alternative predictive algorithms, to assess proteomic predictors of lung cancer risk.

Best practices for peptide measurement and guidelines for publication of peptide and protein identification have been published for the research community.

KEY POINTS:

This evidence review has been updated regularly, with the most recent literature review performed through September 13, 2023.

Summary of Evidence

For individuals with newly diagnosed NSCLC and wild-type EGFR variant status who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes retrospective studies and a prospective nonrandomized study. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. No published studies were identified that assessed the prognostic use of VeriStrat proteomic testing in newly diagnosed stage I or II NSCLC. For individuals with newly diagnosed advanced NSCLC and EGFR-negative variant status without prior systemic therapy, five studies have assessed the use of VeriStrat (“good” or “poor”) as a prognostic test to discriminate between overall survival (primary) progression-free survival (secondary) outcomes. All studies were retrospective and intended to validate the extent to which the VeriStrat proteomic classification correlated with overall survival or progression-free survival. Only one of the five studies reported the percentage of participants who were EGFR-negative, but it did not report outcomes based on variant status. One observational, nonrandomized study with prospective sample collection for proteomic testing before NSCLC treatment reported the percentage of participants who were EGFR-negative, but it did not report outcomes based on variant status. This was also the only study that included a first-line treatment consistent with current guideline-based recommendations-platinum-doublet-based chemotherapy plus cisplatin or carboplatin plus pemetrexed. The VeriStrat classification was not used to direct the selection of treatment in any of the clinical trials from which the validation samples were derived. Disposition of populations with variant status “not reported” was generally not clear and could not be construed as “unknown” when wild-type or positive were reported. No studies were identified that used VeriStrat proteomic testing to inform therapeutic options for patients with stage I or II NSCLC if surgery or surgery plus radiotherapy have been completed or who were upstaged as a result of surgical findings. No studies were identified that used VeriStrat proteomic testing to inform therapeutic options for patients with stage I or II NSCLC who were considered medically inoperable. No studies were identified that used VeriStrat proteomic testing to predict response to first-line targeted therapies or first-line chemotherapy in patients with newly diagnosed advanced NSCLC. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with newly diagnosed NSCLC and unknown EGFR variant status who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes an RCT, four retrospective studies and a prospective study. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. All study populations were either unselected for EGFR-variant status or status was expressly reported as unknown in conjunction with negative or positive status reports. None of the studies that reported unknown EGFR-variant status reported outcomes for the proteomic score based on unknown EGFR-variant status. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with NSCLC and wild-type EGFR variant status and disease progression after first-line systemic therapy who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes an RCT. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. No studies were identified that reported or analyzed outcomes using the proteomic test as a prognostic tool in EGFR-negative variant status populations. The evidence includes an RCT (PROSE) using proteomic testing to predict response to erlotinib compared with chemotherapy as second-line treatment for patients with stage IIIB or IV NSCLC, stratified by performance status, smoking history, treatment center, and (masked) pretreatment VeriStrat classification. In a multivariable model to predict overall survival, which included clinical characteristics and EGFR-variant status, VeriStrat classification was significantly associated with overall survival (HR for VeriStrat “good” vs “poor,” 1.88; 95% CI, 1.25 to 2.84; p=0.003). However, 62% of the combined study population was EGFR-negative. A retrospective analysis was also performed on the MARQUEE trial, a phase III RCT in patients with stage IIIB or IV nonsquamous NSCLC, comparing patient response to erlotinib in conjunction with either tivantinib or a placebo; patients were stratified by EGFR/KRAS mutation status, gender, smoking history, and treatment history. Protocol treatments were subsequently discontinued by 93% of patients, and the trial was discontinued after prespecified interim futility analysis. In a multivariable model to predict overall survival, which included clinical characteristics and EGFR-variant status, VeriStrat classification was significantly associated with overall survival (hazard ratio for VeriStrat “good” vs “poor,” 0.52; 95% confidence interval, 0.40 to 0.67; p<0.001). 90% of the combined study population was EGFR-negative. An interaction between treatment and VeriStrat status was significant for multivariable analysis including EGFR status (p=0.036) but not significant for multivariable analysis including both EGFR and KRAS status (p=0.068). Currently, the use of erlotinib in patients unselected for the presence or absence of an EGFR-sensitizing variant is not standard clinical practice. It is recommended that variant status is determined, if not previously ascertained, before selecting treatment after progression or recurrence. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with NSCLC and unknown EGFR variant with disease progression after first-line systemic therapy who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes three retrospective studies and two RCTs. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The use of VeriStrat as a prognostic test to discriminate between good and poor survival outcomes was assessed in three retrospective studies intended to validate the extent to which VeriStrat proteomic classification correlates with overall survival or progression-free survival. The VeriStrat classification was not used to direct treatment selection in any of the trials from which the validation samples were derived. None of the clinical trials from which the samples for VeriStrat proteomic classification were derived used a therapy consistent with current guidelines-based recommendations. The populations in all three studies were unselected for EGFR-variant status. In the PROSE RCT, using a multivariable model to predict overall survival, which included clinical characteristics and EGFR-variant status, VeriStrat classification was significantly associated with overall survival (HR for VeriStrat “good” vs “poor,” 1.88; 95% CI, 1.25 to 2.84; p=0.003). However, 32.6% of the combined study population had unknown EGFR status. In the EMPHASIS RCT, there were no significant differences in progression-free survival or overall survival among patients with VeriStrat “good” status receiving erlotinib or chemotherapy or among patients with VeriStrat “poor” status receiving erlotinib or chemotherapy. The results of the EMPHASIS RCT were restricted to squamous NSCLC histology. Currently, the use of erlotinib in patients unselected for the presence or absence of an EGFR-sensitizing variant is not standard clinical practice. It is recommended that variant status is determined, if not previously ascertained, before selecting treatment after progression or recurrence. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network (v3.2023) guidelines on the management of non-small cell lung cancer (NSCLC) recommend routine testing for EGFR variants in patients with advanced or metastatic nonsquamous NSCLC (category 1 recommendation) and consideration for EGFR-variant testing in patients with metastatic squamous NSCLC who were never smokers or with small biopsy specimens or mixed histology (category 2A recommendation).The guideline also recommends molecular testing for EGFR mutation on diagnostic biopsy or surgical resection sample to ensure the EGFR mutation results are available for adjuvant treatment decisions for patients with stage IIB-IIIA or high-risk stage IB-IIA NSCLC. Recommendations for first-line treatment for EGFR-positive patients with advanced or metastatic NSCLC, and EGFR-negative or -unknown patients as well as for patients in either category who have progressed on therapy are provided.

American Society of Clinical Oncology

In 2023, the American Society of Clinical Oncology updated its ‘living’ clinical practice guidelines. Recommendations for patients with stage IV NSCLC are provided as separate guidelines for patients with and without driver mutations. The guideline on treatment of NSCLC with driver mutations discusses treatments for patients with positive biomarkers (e.g., EGFR, ALK, ROS1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions). The guideline on treatment of NSCLC without driver mutations discusses therapy for patients with stage IV NSCLC without driver alterations in EGFR or ALK and with programmed death ligand 1 (PD-L1) tumor proportion score status that is known to the clinician.

The Society (2018) endorsed clinical practice guidelines from other medical associations (College of American Pathologists, International Association for the Study of Lung Cancer, Association for Molecular Pathology) addressing molecular testing for the selection of patient with lung cancer for treatment with targeted tyrosine kinase inhibitors.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Proteomic Testing, VeriStrat®, matrix assisted laser desorption ionization, MALDI, mass spectrometry, Non-small cell lung cancer, NSCLC

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The commercially available proteomic test (VeriStrat®; Biodesix) is available under the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply. Refer to member’s benefit plan. 

CURRENT CODING:

CPT Codes:

REFERENCES:

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POLICY HISTORY:

Medical Policy Panel, October 2014

Medical Policy Group, October 2014 (1): New policy, previously only listed on the Investigational Listing; remains investigational

Medical Policy Administration Committee, November 2014

Available for comment October 24 through December 7, 2014

Medical Policy Panel, October 2015

Medical Policy Group, October 2015 (3):  2015 Updates to Description, Key Points, Governing Bodies, Coding & References; no change in policy statement

Medical Policy Group, November 2015: 2016 Annual Coding Update. Created previous coding section and moved CPT 84999 to this section.

Medical Policy Group, December 2015 (4): 2016 Update to Key Points; update to literature review search date.

Medical Policy Panel, February 2017

Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points, and References; no change to policy statement.

Medical Policy Panel, November 2017

Medical Policy Group, November 2017 (3): 2017 Updates to Description, Key Points, and References; no change to Policy statement.

Medical Policy Panel, April 2018

Medical Policy Group, May 2018 (2): 2018 Updates to Title, Description, Key Points, Key Words, and References; no change to Policy Statement.

Medical Policy Panel, November 2018

Medical Policy Group, November 2018 (9): 2018 Updates to Description and Key Points.  No change to policy statement.

Medical Policy Group, December 2018: 2019 Coding updated.  Added new CPT code 0080U to Current Coding.

Medical Policy Panel, November 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, November 2020

Medical Policy Group, November 2020 (9): 2020 Updates to Key Points, References. No change to policy statement.

Medical Policy Panel, December 2021

Medical Policy Group, December 2021 (9): 2021 Updates to Description, Key Points, References. Policy statement updated to remove “not medically necessary,” no change to policy intent.  

Medical Policy Panel, November 2022

Medical Policy Group, November 2022 (9): 2022 Updates to Description, Key Points, References. Removed CPT code 0080U from this policy (see MP 711: Plasma-Based Proteomic Screening of Pulmonary Nodules for this code/technology). Removed Previous Coding section. No change to policy statement.

Medical Policy Panel, November 2023

Medical Policy Group, November 2023 (5): Updates to Description, Key Points, Benefit Application, and References. No change to Policy Statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.