Clinical UM Guideline
|Subject:||Beta Interferons or Glatiramer Acetate for Treatment of Multiple Sclerosis|
|Guideline #:||CG-DRUG-03||Current Effective Date:||01/01/2014|
|Status:||Reviewed||Last Review Date:||08/08/2013|
A number of drugs are available to treat various aspects of multiple sclerosis (MS). Interferon beta agents (i.e., Avonex®, Biogen Idec, Inc., Cambridge, MA; Rebif®, EMD Serono, Inc., Rockland, MA; Betaseron®, Bayer HealthCare Pharmaceuticals Inc., Montville, NJ; Extavia®, Novartis Pharmaceuticals Corp., East Hanover, New Jersey), and glatiramer acetate (Copaxone®, TEVA Neuroscience, Inc., Kansas, MO) are administered in an effort to decrease the relapse rate and delay the progression of the disease. For the majority of individuals with MS, the mainstay of treatment focuses on the use of interferon beta (IFN-B) agents or glatiramer acetate. This guideline focuses on the use of IFN beta-1a (Avonex, Rebif), IFN beta-1b (Betaseron, Extavia) and glatiramer acetate (Copaxone) for the treatment of MS.
I. Beta Interferons (IFN beta-1a [Avonex, Rebif] or IFN beta-1b [Betaseron, Extavia])
Treatment of MS with IFN beta-1a or IFN beta-1b is considered medically necessary for individuals with any of the following conditions:
Not Medically Necessary:
Treatment of MS with IFN beta-1a or IFN beta-1b is considered not medically necessary for individuals with either of the following conditions:
Treatment of MS with IFN beta-1a or IFN beta-1b in combination with glatiramer acetate or in combination with natalizumab is considered not medically necessary for all conditions.
II. Glatiramer acetate (Copaxone)
Treatment of MS with glatiramer acetate is considered medically necessary for individuals with relapsing-remitting MS (RRMS), including those who have experienced a first clinical episode and have MRI features consistent with MS.
Not Medically Necessary:
Treatment of MS with glatiramer acetate is considered not medically necessary for individuals with either of the following conditions:
Treatment of MS with glatiramer acetate in combination with any IFN-B agent or in combination with natalizumab is considered not medically necessary for all conditions.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
|J1595||Injection, glatiramer acetate, 20 mg [Copaxone]|
|J1826||Injection, interferon beta-1a, 30 mcg [Avonex, Rebif]|
|J1830||Injection, interferon beta-1b, 0.25 mg [Betaseron, Extavia]|
|Q3027||Injection, interferon beta-1a, 1 mcg for intramuscular use [Avonex, Rebif]|
|Q3028||Injection, interferon beta-1a, 1 mcg for subcutaneous use [Avonex, Rebif]|
|S9559||Home injectable therapy, interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment; per diem|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2014]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
MS is an autoimmune disease of the central nervous system (CNS). In MS, inflammation of nervous tissue causes the loss of myelin, a fatty material that acts as a protective insulation for the nerve fibers in the brain and spinal cord. This demyelination leaves multiple areas of hard scarred tissue (plaques) along the covering of the nerve cells. Another characteristic of MS is the destruction of axons, which are the long filaments that carry electric impulses away from a nerve cell. The demyelination and axon destruction disrupts the ability of the nerves to conduct electrical impulses to and from the brain, and produces the various symptoms. Common symptoms of the disease include fatigue, numbness, coordination and balance problems, bowel and bladder dysfunction, emotional and cognitive changes, spasticity, vision problems, dizziness, sexual dysfunction, and pain. Classifications of MS are relapsing remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS), and secondary progressive MS (SPMS). Most individuals with MS have a relapsing course and their first attack may present as a clinically isolated syndrome (CIS). A CIS is a single demyelinating episode with consistent MRI findings (indicating inflammation/demyelination in one or more sites in the CNS). Individuals with this syndrome are at high risk for developing clinically definite MS.
The treatment goal for MS is to prevent relapses and progressive worsening of the disease. To date, a cure remains elusive and current therapies fail to reverse degenerative processes and deficits. Current disease-modifying drugs are most effective for the relapsing-remitting form of MS and less effective for secondary progressive decline. The American Academy of Neurology (AAN), the Multiple Sclerosis Council for Clinical Practice Guidelines and the National Multiple Sclerosis Society suggest starting disease-modifying therapy (drug treatment) in those with relapsing remitting disease and recent relapses; however, opinions may vary widely on when to initiate treatment (AAN, 2002). Generally, disease-modifying therapy should be considered early in the disease course.
IFN beta-1a, IFN beta-1b and glatiramer acetate are all United States Food and Drug Administration (FDA) approved disease-modifying therapies (DMTs). In 1993, the first DMT, IFN beta-1b (Betaseron) was approved for RRMS to reduce the rate and severity of relapses. This was followed by approval of IFN beta-1a (Avonex) in 1996 and glatiramer acetate (Copaxone) in 1997. Another formulation of IFN beta-1a (Rebif) was approved in 1998 in Europe and Canada and in 2002 in the United States. These drugs have been shown to delay the progression of MS, reduce the incidence of relapses and also reduce the MRI activity thought to be linked to the underlying inflammation of the disease (Freedman 2008). In August 2009, the FDA approved Extavia, a new branded version of interferon beta-1b which has the same medicinal product as Betaseron.
IFN beta-1a and IFN beta-1b are FDA approved for relapsing forms of MS. In addition, the efficacy of IFN beta-1a and IFN beta-1b has been demonstrated in individuals who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer acetate is FDA approved for RRMS and for those who have experienced a first clinical episode and have MRI features consistent with MS.
The AAN (2002) recommends beta interferon (beta 1a and beta 1b) for the management of individuals with RRMS, relapsing forms of secondary progressive MS, and in those with MS or with a CIS who are at high risk of developing clinically definite MS. The AAN (2002) notes that there are several consistent Class I studies (prospective, randomized, controlled clinical trials with masked outcome assessments, in a representative population) in which beta interferon has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in individuals with MS or with CIS who are at high risk for developing MS (Type A recommendation). A "Type A recommendation" is the highest rating assigned by the AAN.
The National Clinical Advisory Board of the National Multiple Sclerosis Society Treatment Recommendations for Physicians (2008) Expert Opinion Paper states that "there are no direct comparative data to allow a fully informed choice of the best immunomodulatory drug class (interferon beta or glatiramer acetate) with which to initiate therapy in relapsing forms of MS."
A recent randomized controlled trial (Lublin and colleagues, 2013) compared efficacy of the combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily to either agent alone in relapsing-remitting multiple sclerosis. A total of 1,008 participants were randomized and followed until the last enrolled participant completed three years of treatment. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. It was reported that combining the two most commonly prescribed therapies for MS (IFN+GA) did not produce a significant clinical benefit over three years. However, an effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences.
Multiple studies have demonstrated the efficacy of the beta interferon products or glatiramer acetate in the treatment of certain types of MS (Comi, 2009; Ford, 2010; Kinkel, 2006; Reder, 2010; Kinkel, 2012). However, current data remains insufficient to make a recommendation regarding the use of one of the beta interferon products (Avonex, Rebif, Betaseron, and Extavia) over another. Also, current data remains insufficient to make a recommendation regarding the use of the beta interferon products (Avonex, Rebif, Betaseron, and Extavia) over glatiramer acetate (Copaxone) in the treatment of RRMS.
Off Label Indications:
Diagnostic criteria for MS have evolved in recent years. Although the diagnosis can be made on clinical grounds alone, MRI of the CNS can support, supplement, or even replace some clinical criteria (Pohlman, 2011). The McDonald Criteria, a tool for the diagnosis of MS, was updated in 2010 by the International Panel on Diagnosis of MS (the Panel). The Panel stressed that the McDonald criteria should only be applied in those individuals who present with a typical CIS suggestive of MS or symptoms consistent with a CNS inflammatory demyelinating disease. This is because the development and validation of the criteria was limited to individuals with such a presentation. The 2010 McDonald criteria are documented in the table below and include clinical presentations as well as additional data needed for MS diagnosis including MRI findings for demonstration of dissemination of CNS lesions in space and time.
The 2010 McDonald Criteria for Diagnosis of MS
Additional Data Needed for MS Diagnosis
|2 or more attacksa; objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attackb.|
2 or more attacksa; objective clinical evidence of one lesion
Dissemination in space, demonstrated by:
1 attacka; objective clinical evidence of two or more lesions
Dissemination in time, demonstrated by:
1 attacka; objective clinical evidence of one lesion (clinically isolated syndrome)
Dissemination in space and time, demonstrated by:
For dissemination in space (DIS):
For dissemination in time (DIT), demonstrated by:
Insidious neurological progression suggestive of MS (PPMS)
1 year of disease progression (retrospectively or prospectively determined) plus 2 of 3 of the following criteriad:
If the Criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is ''MS''; if suspicious, but the Criteria are not completely met, the diagnosis is ''possible MS''; if another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is ''not MS.''
aAn attack (relapse; exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurological examination, but some historical events with symptoms and evolution characteristic for MS, but for which no objective neurological findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurological examination, visual evoked potential response in patients reporting prior visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurological symptoms.
bClinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of documented objective neurological findings, can include historical events with symptoms and evolution characteristics for a prior inflammatory demyelinating event; at least 1 attack, however, must be supported by objective findings.
cNo additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these Criteria. If imaging or other tests (for instance, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS, and alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence must be present to support a diagnosis of MS.
dGadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with brainstem or spinal cord syndromes.
MS = multiple sclerosis; CNS = central nervous system; MRI = magnetic resonance imaging; DIS = dissemination in space; DIT = dissemination in time; PPMS = primary progressive multiple sclerosis; CSF = cerebrospinal fluid; IgG = immunoglobulin G.
2010 McDonald MRI Criteria for Demonstration of DIS:
Based on Swanton et al 2006, 2007.
2010 McDonald MRI Criteria for Demonstration of DIT:
Based on Montalban et al 2010.
MRI = magnetic resonance imaging; DIT = lesion dissemination in time.
2010 McDonald Criteria for Diagnosis of Multiple Sclerosis in Disease with Progression from Onset:
aIf a subject has a brainstem or spinal cord syndrome, all symptomatic lesions are excluded from the Criteria.
Attacks: The appearance of new symptoms or the aggravation of old ones, lasting at least twenty-four hours (synonymous with exacerbation, relapse, flare-up, or worsening); usually associated with inflammation and demyelination in the brain or spinal cord.
Clinical lesion: An area of inflamed or demyelinated central nervous system tissue; synonymous with plaque.
Clinically isolated syndrome (CIS): A single demyelinating episode with consistent MRI findings (indicating inflammation/demyelination in one or more sites in the CNS). Individuals with this syndrome are at high risk for developing clinically definite MS.
Primary progressive MS (PPMS): A clinical course of MS characterized by progression of disability from onset without superimposed relapses.
Progressive relapsing MS (PRMS): A primary progressive clinical course of MS characterized by clear, acute relapses, with or without full recovery from those relapses.
Relapsing-remitting MS (RRMS): A clinical course of MS characterized by clearly defined, acute relapses with full or partial recovery; no disease progression or worsening of disability develops between relapses.
Secondary progressive MS (SPMS): A clinical course of MS demonstrating sustained progression of physical disability occurring separately from relapses in individuals who previously had RRMS.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Web Sites for Additional Information|
Interferon Beta Agents
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|01/01/2014||Updated Coding section with 01/01/2014 HCPCS changes; removed Q3025, Q3026 deleted 12/31/2013.|
|Reviewed||08/08/2013||Medical Policy & Technology Assessment Committee (MPTAC) review. Rationale and Reference sections updated.|
|Reviewed||08/09/2012||MPTAC review. Discussion and Reference sections updated.|
|Reviewed||08/18/2011||MPTAC review. Description, Discussion (including McDonald Criteria), Reference, and Definition sections updated.|
|01/01/2011||Updated Coding section with 01/01/2011 HCPCS changes; removed code J1825 deleted 12/31/2010.|
|Revised||08/19/2010||MPTAC review. Clinical indication section reformatted. Clarified glatiramer acetate not medically necessary statement by removing duplicative secondary progressive MS wording. References and discussion updated.|
|Revised||08/27/2009||MPTAC revision. Drug brand names removed from clinical indications section. Removed table of FDA approved drugs with dosing and labeling information from discussion section. Removed not medically necessary statement regarding dosages greater than approved by the U.S. Food and Drug Administration (FDA). Description, discussion, references, and index updated. Information regarding Extavia added to document contents.|
|Revised||05/21/2009||MPTAC revision. Clinical indications for glatiramer acetate updated to include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Deletion of section of not medically necessary statement for glatiramer acetate referring to those with an initial demyelinating event. Place of service section deleted. Discussion and references updated.|
|Reviewed||02/26/2009||MPTAC review. Discussion and references updated. Moved "Summary of the FDA Approved Pharmaceutical Agents for the Treatment of MS" and the "International Panel Criteria" charts to the discussion/general information section of the document. Title updated.|
|Reviewed||08/28/2008||MPTAC review. Description, discussion and references updated.|
|04/01/2008||References updated to reflect change from USP DI® to new DrugPoints® compendia.|
|Reviewed||08/23/2007||MPTAC review. Title revised. Clinical indications clarified. Definitions and references updated.|
|Revised||09/14/2006||MPTAC revision. Update of guideline to include concomitant usage of beta interferons and glatiramer acetate or natalizumab is considered not medically necessary.|
|Revised||06/08/2006||MPTAC revision. Update of McDonald diagnostic criteria. Coding and references updated. No change to guideline position.|
|New||07/14/2005||MPTAC initial guideline development.|