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Melanoma Vaccines

Policy Number: MP-604

Latest Review Date: June 2017

Category: Medical

Policy Grade: B

DESCRIPTION OF PROCEDURE OR SERVICE:

Tumor vaccines are a type of active immunotherapy that attempts to stimulate the patient’s own immune system to respond to tumor cell antigens. A wide range of vaccine types are available including use of autologous tumor cells, allogeneic tumor cells, and tumor-specific moieties including peptides, gangliosides, and DNA plasmids. A variety of mechanisms appear to exist as possible obstacles to successful active immunotherapy using vaccines. Current areas of investigation include new and different vaccine preparations, as well as various forms of immune modulation to enhance vaccine effectiveness.

Vaccines using crude preparations of tumor material were first studied by Ehrlich over 100 years ago. However, the first modern report to suggest benefit in cancer patients did not appear until 1967. Melanoma has been viewed as a particularly promising target for vaccine treatment because of its immunologic features, which include the prognostic importance of lymphocytic infiltrate at the primary tumor site, the expression of a wide variety of antigens, and the occasional occurrence of spontaneous remissions. Melanoma vaccines can be generally categorized or prepared in the following ways:

  • Whole-cell vaccines prepared using melanoma cells or crude subcellular fractions of melanoma cell lines
  • Autologous whole-cell vaccines in which tumor cells are harvested from the tissue of excised cancers, irradiated, and potentially modified with antigenic molecules to increase immunogenicity and made into patient-specific vaccines (e.g., M-Vax®, AVAX Technologies)
  • Autologous heat-shock protein-peptide complexes vaccines in which a patient’s tumor cells are exposed to high temperatures and then purified to make patient-specific vaccines (e.g., Oncophage®, Antigenics Inc.), and
  • Allogeneic whole-cell vaccines in which intact or modified allogeneic tumor cell lines from other patients are lysed by mechanical disruption or viral infection and used to prepare vaccine (e.g., Canvaxin®, CancerVax Corp.; or Melacine®, University of Southern California).
  • Dendritic cell vaccines in which autologous dendritic cells are pulsed with tumor-derived peptides, tumor lysates, or antigen encoding RNA or DNA to produce immunologically enhanced vaccines.
  • Peptide vaccines consisting of short, immunogenic peptide fragments of proteins (e.g., melanoma antigen E [MAGE]; B melanoma antigen [BAGE]) used alone or in different combinations to create vaccines of varying antigenic diversity, depending on the peptide mix.
  • Ganglioside vaccines in which glycolipids present in cell membranes are combined with an immune adjuvant (e.g., GM2) to create vaccines.
  • DNA vaccines created from naked DNA expression plasmids.
  • Viral vectors in which DNA sequences are inserted into attenuated viruses for gene delivery to patient immune systems.
  • Anti-idiotype vaccines made from monoclonal antibodies with specificity for tumor antigen-reactive antibodies.

POLICY:

Effective for dates of service on or after June 15, 2017:

 

Imlygic® (talimogene laherparepvec) may be considered medically necessary for treatment as a direct intralesional injection into recurrent, unresectable melanoma when any of the following indications are met:

  1. Stage III disease in-transit; or
  2. Local/satellite recurrence of disease; or
  3. In-transit recurrence of disease.

Imlygic® (talimogene laherparepvec) is considered not medically necessary and investigational when the above criteria are not met, and for all other indications.

Melanoma vaccines, with the exception of Imlygic® (talimogene laherparepvec) are considered not medically necessary and investigational.

__________________________________________________________________

Effective for dates of service August 22, 2015 through June 14, 2017:

 

Melanoma vaccines are considered not medically necessary and investigational.

KEY POINTS:

Herpes Simplex Derived Immunotherapy

On October 27, 2015, Amgen, Inc.'s talimogene laherparepvec (IMLYGIC, Thousand Oaks, CA) received manufacturing approval from the U.S. Food and Drug Administration (FDA) based on results from a Phase III clinical trial. Andtbacka and colleagues conducted a Phase III randomized, open-label clinical trial, known as OPTiM, using the first-in-class IMLYGIC (T-VEC). In early clinical trials, T-VEC, based on a modified herpes simplex virus, boosted replication and expression of granulocyte macrophage colony-stimulating factor (GM-CSF) with responses observed in both injected and uninjected lesions. GM-CSF induces tumor-specific T-cell responses. A total of 436 individuals with unresectable stage IIIB to IV metastatic melanoma were randomized 2:1 to the intralesional T-VEC arm (n=295) or to subcutaneous recombinant GM-CSF (n=141). T-VEC was administered once every 3 weeks on average and GM-CSF was administered subcutaneously once a day for 14 days in 28-day cycles. After 24 weeks of treatment, injections continued until disease progression, intolerability, lack of response (T-VEC arm only), or complete remission. After 12 months, those with stable or responsive disease could continue receiving treatment for up to 6 additional months. Median follow-up was 44.4 months (range, 32.4-58.7 months) and the primary outcome of interest was durable response rate (DRR) lasting ≥ 6 months. DRR was significantly higher in the T-VEC arm (16.3%; 95% confidence interval [CI], 12.1-20.5%) than in the GM-CSF arm (2.1%; 95% CI, 0-4.5% [Odds Ratio [OR], 8.9; p<0.001]). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4-31.5% vs 5.7%; 95% CI, 1.9-9.5%). Median overall survival (OS) was 23.3 months (95% CI, 19.5-29.6 months) with T-VEC and 18.9 months (95% CI, 16.0-23.7 months) with GM-CSF (hazard ratio [HR], 0.79; 95% CI, 0.62-1.00; p=0.051); the difference in OS was not significantly different. The most common adverse events in the T-VEC arm were fatigue, chills and pyrexia. Cellulitis was the only grade 3 or 4 adverse event occurring in 2.1% of the T-VEC treated arm; no treatment-related deaths were reported. Factors influencing the outcomes of this study design include the lack of blinding, shorter duration of treatment of GM-GSF, and the use of GM-GSF, which also has no impact on overall survival, as a single agent comparator during the study period. Although the FDA has granted T-VEC's approval for the intralesional treatment of injectable, unresectable, melanoma lesions in the skin and lymph nodes, blinded Phase III clinical trials demonstrating a significant improvement in OS are warranted. Exploratory subset analysis of the pivotal clinical trial suggests that T-VEC's response is greater in less advanced disease when measured by the primary outcome of durable response rate.

In a 2011 systematic review and meta-analysis of 4375 patients in 56 phase II and phase III studies, no evidence was found that vaccine therapy yields better overall disease control or OS compared with other treatments. Currently, there are 12 phase 3 clinical studies that have evaluated melanoma vaccines: four using allogeneic vaccines, two autologous whole-cell vaccines, two ganglioside vaccines, one autologous heat shock protein, and three peptide vaccines—one pulsed with dendritic cells, one administered with ipilimumab, and one administered with concomitant IL-2. In two studies, vaccine treatments appeared to demonstrate superior performance in unique populations identified during post hoc data evaluation. However, no published study to date has shown a statistically significant survival benefit in the general population selected for study. In two reports, outcomes using vaccines appeared inferior to those observed in controls. Table 1 provides a summary of trials that showed lack of efficacy of melanoma vaccines.

Several explanations have been offered as to why melanoma vaccines have not produced clinically significant improvements in clinical outcomes. One possible mechanism is immune ignorance and the ability of melanoma cells to escape detection through loss of antigens or loss of HLA expression. A second mechanism is immune tolerance. This may result from the ability of the melanoma tumor to prevent a local accumulation of active helper and/or effector T cells as a result of high interstitial pressure in the tumor or lack of appropriate adhesion molecular on tumor vasculature. This may also occur as a result of normal down-regulation of the immune system at the site of T-cell tumor interaction. A wide range of immune-modulating techniques are being explored to find mechanisms for enhancing the immune response induced by tumor vaccines. In 2011, one potential solution to this problem is to use molecular profiling to identify relevant immune resistance in the tumor microenvironment. If confirmed in future studies, this approach toward identifying subsets of patients likely to benefit from specific treatment choices may help improve treatment outcomes with the use of tumor vaccines.


Table 1 - Phase III Randomized Controlled Trials of Vaccine Therapy Evaluating Cancer Outcomes

Author

Patient Population

Vaccine

Control

Results

Comment

Livingston et al (1994)

Stage III

(N=122)

GM2/BCG

BCG

DFS and OS showed no statistically significant differences

Patients with no pretreatment anti-GM2 antibody showed improved PFS with vaccine

Wallack et al (1998)

Stage III

(N=217)

Vaccinia melanoma oncolysate

Vaccinia oncolysate from normal cell

DFS and OS showed no statistically significant differences

Kirkwood et al (2001)

Stage IIB/III

(N=774)

Ganglioside GM2-KLH21 (GMK)

Interferon alfa

Trial closed after interim analysis indicated GMK inferiority

Sondak et al (2002)

Stage II

(N=600)

Allogeneic melanoma vaccine (Melacine®)

Observation

No evidence of DFS

Patients with ³2 HLA matches showed improved PFS

Hersey et al (2002)

Stage IIB/III

(N=700)

Vaccinia melanoma oncolysate

Observation

Recurrence-free and OS not statistically improved in vaccine patients

Morton et al (2006)

Stage III

(N=1160)

Canvaxin® + BCG + placebo

BCG + placebo

Trial closed after interim analysis indicated Canvaxin® inferiority

Morton et al (2006)

Stage IV

(N=496)

Canvaxin® + BCG + placebo

BCG + placebo

Trial closed after interim analysis showed lack of efficacy

Mitchell et al (2007)

Stage III

(N=604)

Allogeneic whole-cell lysate administered with Detox™ (Melacine®) + interferon alfa

Interferon alfa

No survival advantage but fewer adverse events in patients on vaccine

Testori et al (2008)

Stage IV

(N=322)

Heat shock protein gp96 complex vaccine (Oncophage®)

Physician’s choice of dacarbazine, temozolomide, IL-2, and/or resection

No survival advantage in patients on vaccine

Schadendorf et al (2006)

Stage IV

(N=108)

Peptide-pulsed dendritic cells

Dacarbazine

Trial closed after interim analysis showed lack of efficacy

Hodi et al (2010)

Stage III or IV

(N=676)

Ipilimumab alone or with GP100

GP100 peptide alone

Ipilimumab showed improved OS with or without GP100 vs GP100 treatment alone

Schwarzentruber et al (2011)

Stage III/IV

(N=185)

GP100 peptide + IL-2

High-dose IL-2

Objective response and increased in patients on vaccine and IL-2 treatment

BGS: bacille Calmette-Guérin; DFS: disease-free survival; GMK: guanylate kinase; HLA: human leukocyte antigen; IL-2: interleukin-2; OS: overall survival.

No new phase III RCT evidence has been published in the period since the last evidence review for this Policy. In recent single-arm series, combinations of immunotherapeutic agents (nivolumab, pegylated interferon) and study vaccines have been investigated in patients with unresectable or resected stage III and IV malignant melanoma. Results from these studies suggest combined immunotherapeutic approaches are tolerable and may have clinical efficacy reflected by tumor regression. However, no valid conclusions can be drawn from this evidence as to the effectiveness of the combinations relative to other treatments.

A randomized, phase II clinical trial published in 2014 evaluated the activity of interleukin-2 (IL-2) alone or IL-2 in combination with allogeneic large multivalent immunogen (LMI) vaccine in patients with stage IV melanoma. The primary objective of this trial was to evaluate the effect of the treatments on progression-free survival (PFS), with a secondary objective to evaluate median OS and one- and two-years rates of OS. The study was halted after enrolling 21 patients after a preplanned analysis established that it was unlikely to meet its primary objective of improved PFS with additional accrual. Per-protocol analysis of data from the 21 accrued patients showed median PFS of 2.20 months in the IL-2 plus LMI group versus 1.95 months in the IL-2 controls (p=NS). Median OS was 11.89 months in the IL-2 plus LMI group and 9.97 months in the IL-2 group (p=NS).

Summary of Evidence

The evidence for melanoma vaccines in patients who have stage II-IV melanoma includes studies on the use of new and different vaccine preparations, as well as on various forms of immune-modulation as potential techniques for enhancing vaccine effectiveness. Relevant outcomes include overall survival, disease-specific survival, and morbid events. Despite considerable activity in numerous studies over the past 20 years, no melanoma vaccine has received U.S. Food and Drug Administration marketing approval. One randomized controlled trial (RCT) of a gp100 melanoma vaccine has reported a significant increase in response rate and progression-free survival. However, several other RCTs have reported no improvements in disease-free survival or overall survival rates with the use of study vaccines. Additionally, other RCTs were closed early due to inferiority of results with study vaccines. Other phase 3 RCTs are underway or in the planning stages to further investigate vaccine preparations to treat malignant melanoma. For use of melanoma vaccines for treatment of patients with stage II-IV melanoma, the body of evidence is insufficient to conclude that anti‒melanoma vaccines of any type, alone or in combination with immunomodulating agents, significantly improve survival outcomes compared with non‒vaccine therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network® (NCCN) 2017 Clinical Practice Guidelines® for melanoma contain a Category 1 recommendation for intralesional treatment of melanoma with T-VEC for stage III disease or local, satellite, and/or in-transit recurrence.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Melanoma vaccine, tumor vaccine, active immunotherapy, M-Vax®, Oncophage®, Canvaxin®, Melacine®, Imlygic®, talimogene laherparepvec

APPROVED BY GOVERNING BODIES:

On October 27, 2015 the FDA approved Amgen, Inc.’s talimogene laherparepvec (Imlygic, Thousand Oaks, CA), the first oncolytic virus therapy for the treatment of melanoma lesions in the skin and lymph nodes.

 

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.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

 

CURRENT CODING: 

CPT Codes:

86849

 Unlisted immunology procedure

J9325

 Injection, talimogene laherparepvec, per 1 million plaque forming units 

 

PREVIOUS CODING:

J9999

 Not Otherwise Classified, Antineoplastic Drugs (when specified as melanoma vaccine, including Imlygic) (Deleted 12/31/16)

 

 

REFERENCES:

1. Andtbacka RH, Agarwala SS, Ollila DW, et al. Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma. Head Neck. 2016 Jul 13. [Epub ahead of print].

2. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015; 33(25):2780-2788.

3.   Blue Cross and Blue Shield Association Technology Evalaution Center. Special Report: Vaccines for the Treatment of Malignant Melanoma. TEC Assessments. 2001;Volume 16, Tab 4.

4.   Chapman PB. Melanoma vaccines. Semin Oncol. Dec 2007; 34(6):516-523.

5.   Chi M, Dudek AZ. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res. Jun 2011; 21(3):165-174.

6.   Cunningham TJ, Olson KB, Laffin R, et al. Treatment of advanced cancer with active immunization. Cancer. Nov 1969; 24(5):932-937.

7.   Eggermont AM. Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer. Aug 2009; 45(12):2087-2090.

8.   Garbe C, Eigentler TK, Keilholz U, et al. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011; 16(1):5-24.

9.   Gajewski TF. Molecular profiling of melanoma and the evolution of patient-specific therapy. Semin Oncol. Apr 2011; 38(2):236-242.

10. Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res. Feb 15 2015; 21(4):712-720.

11. Hersey P, Coates AS, McCarthy WH, et al. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol. Oct 15 2002; 20(20):4181-4190.

12. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. Aug 19 2010; 363(8):711-723.

13  Hoeller C, Michielin O, Ascierto PA, et al. Systematic review of the use of granulocyte-macrophage colony-stimulating factor in patients with advanced melanoma. Cancer Immunol Immunother. 2016; 65(9):1015-1034.

15. Imlygic® Product Information (PI) Label. Thousand Oaks, CA. October 27, 2015. Available at: www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM469575.pdf.

14. Jha G, Miller JS, Curtsinger JM, et al. Randomized phase II study of IL-2 with or without an allogeneic large multivalent immunogen vaccine for the treatment of stage IV melanoma. Am J Clin Oncol. Jun 2014; 37(3):261-265.

15. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. May 1 2001; 19(9):2370-2380.

16.  Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther. Mar 2008; 8(3):315-323.

17.  Livingston PO, Adluri S, Helling F, et al. Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine. Nov 1994; 12(14):1275-1280.

18.  Massaoka MH, Matsuo AL, Figueiredo CR, et al. A subtraction tolerization method of immunization allowed for Wilms' tumor protein-1 (WT1) identification in melanoma and discovery of an antitumor peptide sequence. J Immunol Methods. Dec 1 2014; 414:11-19.

19. Mitchell MS, Abrams J, Thompson JA, et al. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma. J Clin Oncol. May 20 2007; 25(15):2078-2085.

20. Morton Dl MN, Thompson JF et al. . An international, randomized phase III trial of bacillus Calmette-Guerin (BCG) plus allogenic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. J Clin Oncol. 2007; 25(18S):8508.

21. National Comprehensive Cancer Network N. Clinical Practice Guidelines in Oncology, Melanoma (v1.2017). www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.

22. Quinn C, Ma Q, Kudlac A, et al. Indirect treatment comparison of talimogene laherparepvec compared with ipilimumab and vemurafenib for the treatment of patients with metastatic melanoma. Adv Ther. 2016; 33(4):643-657.

22. Ray S, Chhabra A, Mehrotra S, et al. Obstacles to and opportunities for more effective peptide-based therapeutic immunization in human melanoma. Clin Dermatol. Nov-Dec 2009; 27(6):603-613.

23. Riker AI, Rossi GR, Masih P, et al. Combination immunotherapy for high-risk resected and metastatic melanoma patients. Ochsner J. Summer 2014; 14(2):164-174.

24.  Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. Sep 2004; 10(9):909-915.

25. Schadendorf D, Ugurel S, Schuler-Thurner B, et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. Apr 2006; 17(4):563-570.

26. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. Jun 2 2011; 364(22):2119-2127.

27. Schwartzentruber DJ LD, Richards J et al. A Phase III multi-institutions randomized study of immunization with the gp100.209-217 (210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. A Phase III multi-institutions randomized study of immunization with the gp100.209-217 (210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. 2009 ASCO Annual Meeting. 2009.

28. Sondak VK, Liu PY, Tuthill RJ, et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol. Apr 15 2002; 20(8):2058-2066.

29. Testori A, Richards J, Whitman E, et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. Feb 20 2008; 26(6):955-962.

30.  Wallack MK, Sivanandham M, Balch CM, et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg. Jul 1998; 187(1):69-77; discussion 77-69.

31. Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013; 31(34):4311-4318.

POLICY HISTORY:

Medical Policy Panel, May 2015

Medical Policy Group, July 2015 (3): New policy created.

Medical Policy Administration Committee, July 2015

Available for comment July 8 through August 22, 2015

Medical Policy Panel, August 2015

Medical Policy Group, August 2015 (3):  Updates to Key Points; no change in policy statement

Medical Policy Panel, June 2016

Medical Policy Group, June 2016 (3): Updated References; no other updates added; no change in policy statement; retiring policy

Medical Policy Group, July 2016 (2): Update to Current Coding section: added J9999 when specified as melanoma vaccine, including Imlygic

Medical Policy Group, December 2016: 2017 Annual Coding Update.  Created Previous Coding section and moved existing code J9999 to this section.

Medical Policy Group, June 2017 (2): Updates to Key Points, Key Words, Approved by Governing Bodies, and References; Policy statement updated to include criteria for Imlygic for intralesional injections for recurrent, unresectable melanoma.

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.