CONTEMPORARY
`
`ISSUES
`
`El
`
`Reducing costs while enhancing quality of
`care in MS
`
`Ilya Kister, MD
`J°hn R‘ C°"°°Y’ MD
`
`8?:de °°
`iiyaidsmenyumcmg
`
`Editorial, page 1532
`
`Supplemental data
`at Neurology.org
`
`ABSTRACT
`The rapid escalation in prices of disease modifying therapies (DMTs) for multiple sclerosis (MS) over
`the past decade has resulted in a dramatic overall increase in the costs of MS related care. In this
`article, we outline various approaches whereby neurologists can contribute to responsible cost con
`tainment while maintaining, and even enhancing, the quality of MS care. The premise of the article is
`that clinicians are uniquely positioned to introduce innovative management strategies that are both
`medically sound and cost efficient. We describe our “top 5” recommendations, imluding strategies
`for customizing relapse treatment; developing alternative dosing schedules for Food and Drug
`Administration approved MS DMTs; using off label therapies for relapse suppression; and limiting
`the use of DMTs to those who clearly fulfill diagnostic criteria, and who might benefit from continued
`use over time. These suggestions are well grounded in the literature and our personal experience,
`but are not always supported with rigorous Class I evidence as yet. We advocate for neurologists to
`take a greater role in shaping clinical research agendas and helping to establish cost effective
`approaches on a firm empiric basis. Neurology° 2016;87:1617-1622
`
`GLOSSARY
`
`DMT = disease-modifyirg thermy; FDA = Food aid Drug Administration; M8 = mult'ple sclerosis; PML = progessive
`rmltifocal leukoenoephalopathy; UBO = unidentified bright object.
`
`There have been considerable advances in the treatment ofmultiple sclerosis (MS) over the past 2 decades, and
`recent evidence suggests that specialized care for patients with MS is associated with “decreased adverse events
`and [decreased] usage of acute and post acute health care resources.”l At the same time, costs of MS care are
`rising, largely because of the rapid escalation in prices of disease modifying therapies (DMTS).2 Insurance
`carriers and specialty pharmacies have responded by sedting to deny or limit payments for costly therapies,
`using “step edits” (a requirement to fail one or more therapies before approving and paying for an alternative
`approved therapy), “tiered formularies” (different copays for DMTs to treat the same disease), and escalating
`copays, deductibles, and coinsurance, so as no transfer more costs to the insured patient. All of these practices
`interfere with shared decision making between patents and their doctors and may have detrimental elfects on
`quality of MS care.:1 In an effort to curtail medical costs, the “Choosing Wisely” campaign’ supported by the
`American Academy of Neurology put forth a list of 5 neurologic practices that could, or should, be eliminated,
`including use of first line DMTs in nonrelapsing, secondary progressive MS. Many in the MS community
`thought that this broad recommendation failed to consider the nuances of which patients with MS might
`benefit from continued use of DMTs.4 An alternative, more presaiptive approach to cost containment is
`to introduce new strategies for managing MS that are medically and economically sound. We outline here
`5 possible strategies, but many others could be proposed as well. Our sugestions, summarized in the table,
`should not be viewed as practice guidelines
`they are not always based on rigorous Class I evidence as yet
`but
`as an effort to set a patient centered, neurologist driven agenda for clinical research in MS that could help
`improve outcomes and decrease costs.
`
`1. Avoid DMT in patients with “improbable MS.” Misdiagnosis of MS is neither a new nor an uncommon phe
`nomenon. It is estimated that 5% to 13% of all “MS patients” do not have MS.5 What is new is the economic
`cost of misdiagnosis associated with use of expensive MS DMTs. The scope of the problem was highlighted by
`a survey published in 2012, in which 112 MS specialists were asked to estimate how many patients were
`referred to them with diagnosis of MS who “almost certainly did not have MS.” The survey responders
`
`From the Department of Neurology (LK), NYU Multiple Sclerosis Care Center, NYU School of Medicine, New York, NY; Department of
`Neurology 0.R.C.). University of Colorado Sdiool of Medicine; and Rocky Mountain MS Center at University of Colorado 0.R.C.), Aurora.
`
`edrelevantbydieatlhorsjfanynrepmvidedatdiemdd‘dnanide.
`'
`GowNmrologmgfixfirIleh-gmffi‘
`logen X 1.3613531?S
`Mylan V. Biogen © 2016 American Academy of Neurology
`1617
`Page 1 0f 6
`2016 American Academy of NeuroloIBRLfiflifl-Mrntflad reproduction of this article is prohibited.
`
`

`

`I Table
`
`Strategy
`
`Cost-containing etretegee: Current evidence and knowledge gaps
`
`Sniper-ting evidence, selected references
`
`1. Avoid DMT h patlmb with
`'hprobdele MS'
`
`Observational studies°'1° show that patients without
`MS typical symptoms/MRI lesions do not develop MS
`
`Areas for further rose-eh
`
`Develop specific MRI criteria for MS (e9. hoorpcrate cortical
`iesions; 'central ve'n' sign): standardize defn'rtions of ”MS typical"
`lesions (9.9.. "Dawson fngers' jottacortieal lesion vs sibcorticai)
`
`|
`
`2. Customize treatment of
`relapse:
`
`Use high dose oral
`mathylprednieolone (1.000
`mg! for MS relapses
`
`Consider plaunaphareoie for
`severe MS ralqnea
`Adverse events from steroid
`use may outweigh benefits it
`mild MS raimees
`
`3. Develop alternative dosh-lg
`strategies for FDA amtoved
`MS DMTe
`
`Natallzumab 300 mg every
`6 8 wk doehg sinilar efficacy
`to every 4 wk dosing
`
`thollmod alternate day
`doehg
`
`Glathmer acetate 20 mg
`alternate day doehg
`
`4. Use off label drugeas DMT: In
`MS
`
`Class | RCT“
`
`Class | RCT for furn‘nent steroid irresponsive CNS
`hflarnrrntory attadtaa
`
`RCTofPLEXasaddontosteroidsfa'severeMSrelepseswidi
`diort andlongtennfolloww
`
`No evidence for long term benefit of steroids; many relapses
`are self fmited
`
`RCT of steroids vs no steroids for mild relapses with short and
`long term follow tp
`
`Multicenter observational study"
`
`Gigo'ng studies to assess risk of PML with extended dose
`reg‘men compared to standard dose regimen
`
`Case reports?“9
`
`Smell scale trialsa”
`
`RCT corrpar‘ng frigol‘lriod 0.5 mg daily vs altemate day
`
`thule for relapehg MS
`
`Tires Class II wages-es and several large observational
`smmssw
`
`Laflunomlda for relqaehg MS
`5. Should DMl's be continued
`indefhltely?
`
`No published studies
`
`RCT of leflnomide vs terifltnomide
`
`Observational, propensity score matched study shows no
`effect in relapse rates but worse disability it previously stable
`patients with M5 M10 discontinue DMTm
`
`Multioenter, randomized. discont'nuation study for patients >55 y
`and norelapsesfor >5yissetto beghrecruitmenth2017
`
`Abbreviations: DMT = disease-modifyhg flierapy; FDA = Food and Drug Adninistration; M8 = multble sclerosis PLEX = piasrnaphsresis; PML = pro-
`greasive multifocal leikoencephalopathy; RCT = randomized clinical trial.
`
`estimated seeing 598 such patients over a 1 year
`period, of whom an estimated 279 patients (47%)
`were receiving a DMT for MS.6
`There are many roads to MS misdiaglosis, but
`one particularly common scenario involves a (poly)
`symptomatic, but neurologically intact patient with
`subcortical “unidentified bright objeas” CUBOs) on
`T2 weighted MRI sequences. Subcortical UBOs are
`nonspecific and are not indudod as part of the formal
`diagnostic criteria in MS? Isolated subcortical UBOs
`are highly uncharacteristic of MS, yet their presence
`often triggers mention of “demyelinating disease” in
`MRI reports.7 Reassuringly, patients without clinical
`history, neurolog'c deficits, or MRI lesions diameter
`istic of MS rarely, if ever, progress to MS.“ 1° There
`fore, such patients should not be prescribed MS
`DMTs, which, in addition to high costs, are associ
`ated with potentially severe side effects. Indeed, one
`of the first natalizumab related fatal cases of progres
`sive multifoarl
`leukoencephalopathy (PML) was
`described in a patient with no MS lesions in the optic
`nerve, brain, or spinal cord at autopsy." Thus, while
`we agree with the concept of early and aggressive
`
`treatment of MS, this approach requires a high degree
`of diagnostic certainty at the onset of treatment.
`An important contributing factor to the high rnis
`diagrosis rates is lack of specific serum or CSF bio
`markers of MS, or even of radiographic criteria for
`differentiating demyelinating lesions from lesions of
`other causes. The existing criteria for MS (Barkhof,
`Swanton) are designed not for diagnosing MS, but
`for
`identifying patients with clinically isolated
`syndrome
`first MS like neurologic event who are
`at high risk of developing MS.” We urgently need
`practical radiographic criteria or other biomarkers for
`ruling out MS in a patient with low pretest probability
`ofthis disease and MS atypical lesions, and ruling in
`patients with clinically or radiologically isolated syn
`dromes that often precede clinical MS. One promising
`strategy is to optimize MRI sequences for detection of
`features sugestive of demyelination, such as central
`veins within lesions. Central veins are found in more
`
`than 40% of dernyelinating lesions, but rarely in
`microvascular disease'2 or migraine,‘4 and are thus par
`ticularly usefirl in distinguishing between MS and the
`nonspecific subcortical
`lesions seen in the other
`
`1618 Page 2 of 6
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`Neurology 87 October 11, 2016
`
`2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
`
`

`

`conditions. Other MRI abnormalities of potential
`utility for MS diagnosis are cortical lesions, which
`are seen in 40% of radiologically isolated syn
`dromes,13 but not in migraine,14 and iron deposition
`within lesions.e5
`
`2. Customize treatment of relapses. Corticosteroids are
`the mainstay for treatment of acute attacks of MS,
`usually delivered as methylprednisolone 1,000 mg
`per day IV for 3 to 5 days, sometimes followed with
`an oral taper. Inadequate oral dosing of corticoste
`roids for acute optic neuritis (prednisone 1 mg/kg
`for 14 days) appears to be ineffective, and even det
`rimental,15 but when oral steroids are given in doses
`that are (near) equivalent to IV, there appears to be
`no significant difference in outcomes of relapses. A
`recent
`randomized trial
`showed that high dose
`methylprednisolone 1,000 mg given orally for 3
`days was noninferior to the same dose given IV.16
`The clinical equivalence is biologically plausible as
`82% of oral methylprednisolone is bioavailable.17
`Oral delivery eliminates the relatively high cost of
`IV infusions ($799.35 for 1 hour of nonchemo
`outpatient infusion at the University of Colorado
`Hospital) and is patient friendly. One logistic
`difficulty is the lack of prepackaged oral high dose
`steroid preparations. To circumvent this problem,
`one could use compounding pharmacies (up to
`500 mg
`of methylprednisolone
`could
`be
`compounded in a single capsule at a cost of $264
`for a 5 day, 10 capsule course; Pine Pharmacy,
`Buffalo, NY), or mix 1,000 mg of
`lyophilized
`methylprednisolone intended for IV infusion ($56.75
`per dose at the University of Colorado Hospital) with
`juices or other flavored drinks to make the concoction
`more palatable. However, there is no evidence that
`Acthar gel (adrenocorticotropic hormone) is in any
`way superior to methylprednisolone for MS relapses
`indirect comparisons
`suggest
`that
`it may be
`associated with more
`adverse
`events18
`and its
`current average wholesale price of $40,840.80 for
`a 5 mL/400 unit bottlee6 makes routine use of this
`product for MS relapses difficult to justify.
`All relapses are counted as equal for purposes of cal
`culating annualized relapse rates in clinical trials, but in
`practice they vary widely in severity. Some relapses are
`mild and self limited, and may be difficult to differen
`tiate from the transient worsening due to physiologic
`or psychologic stressors (pseudo relapses). It is uncer
`tain whether risk of an adverse event from steroids out
`weighs potential benefits of
`treatment
`in such
`instances. However, approximately half of relapses
`result in persistent deficits, and nearly a third in
`marked neurologic deterioration (sustained $1 point
`increase on the Expanded Disability Status Scale).19,20
`Clearly, there is room for improvement in managing
`
`steroid nonresponsive MS relapses. IV immunoglobu
`lin has been subjected to rigorous trials with disap
`pointing results. IV immunoglobulin did not benefit
`recovery from acute optic neuritis when used as a solo
`agent,21 and it did not appreciably improve postrelapse
`outcomes when used as an add on to steroids.22 Plas
`mapheresis, however, has shown benefit for fulminant,
`steroid unresponsive CNS inflammatory attacks in
`a Class I, randomized, sham controlled trial.23 It would
`be worthwhile to conduct a similar trial for severe MS
`relapses to determine whether plasmapheresis can
`improve long term outcomes in MS, thereby poten
`tially justifying the initial investment.
`
`3. Develop alternative dosing strategies for Food and
`Drug Administration–approved MS DMTs. Efficacy of
`Food and Drug Administration (FDA) approved
`DMTs has been demonstrated in large randomized tri
`als, but dose and schedule selection for these agents has
`not always been evidence based. For example, glatiramer
`acetate is now believed to exert its action through
`a broad range of mostly long term effects24 that would
`not necessarily require daily administration as
`in
`the pivotal
`trials. Indeed, 2 small scale studies of
`glatiramer acetate 20 mg every other day suggest
`similar efficacy, but better tolerability, of alternate day
`dosing compared to daily dosing,25,26 and glatiramer
`acetate is now marketed as 40 mg 3 times weekly
`based on similar outcomes as 20 mg daily.e7 Another
`candidate for frequency reduction is fingolimod, whose
`half life for a 0.5 mg capsule taken daily is 6 to 9
`days, and its presumed mechanism of action is via
`sequestration of lymphocytes within lymph nodes.27
`There is anecdotal support for fingolimod’s efficacy at
`lower frequency (e.g., every other day) based on our
`experience
`and case
`reports.28,29 The
`ongoing,
`industry sponsored trial of 0.25 mg vs 0.5 mg daily
`dosing of
`fingolimod vs glatiramer acetate 20 mg
`daily30 will address the question of whether each
`fingolimod pill could be halved without sacrificing
`efficacy, but not whether the number of pills could
`be halved. From a cost of care perspective, however,
`a noninferiority trial of alternate day vs daily dosing of
`fingolimod would be preferable. Absent such a trial,
`clinicians could systematically collect and publish
`observational
`data
`on
`their
`patients
`receiving
`fingolimod on an alternate day schedule.
`A particularly important example of a DMT for
`which alternate dosing may not only be cost saving,
`but also life saving is natalizumab, a monoclonal anti
`body that blocks lymphocyte attachment to vascular
`cell adhesion molecule receptors on endothelial surfa
`ces, thereby blocking entry of activated T and B lym
`phocytes into the CNS. Natalizumab is approved for
`every 28 days dosing, yet vascular cell adhesion mol
`ecule receptor saturation of .50% is maintained for
`
`Neurology 87 October 11, 2016
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`
`Page 3 of 6
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`

`8 weeks or more after infusion.31 This observation
`may help explain why disease reactivation is virtually
`never seen less than 8 weeks after the last natalizumab
`infusion.32,33 An investigator initiated, multicenter
`observational study compared efficacy of natalizumab
`dosing interval extended up to 8 weeks and 5 days in
`905 patients with standard, every 28 days natalizu
`mab dosing in 1,093 patients.34 Both groups had
`excellent response to natalizumab, and the extended
`dose group had even fewer relapses and new T2 le
`sions than the standard interval dose group. Despite
`higher risk factors for development of PML in the
`extended dosing group (e.g., higher percentage on
`individuals exposed to the JC virus that causes
`PML, longer exposure to natalizumab, and higher
`use of prior immunosuppression), no cases of PML
`have been observed in the extended dose group to
`date, while 4 cases were seen in the standard fre
`quency group. Thus, preliminary evidence suggests
`that less frequent dosing of natalizumab may be
`a safer, yet highly effective approach that also reduces
`the cost of this very expensive therapy by up to 50%.
`
`4. Off-label use of DMTs for MS. Presently, the main
`driver of MS costs is the direct costs for the DMTs,2,35
`whose sales have more than doubled in the last few
`years.2 The average annual DMT price in the United
`States now exceeds $60,000 per patient year.2,e1 A highly
`effective and significantly less expensive alternative for
`relapse suppression in MS is rituximab, a monoclonal,
`anti CD20 antibody that is FDA approved for treatment
`of certain malignancies (non Hodgkin lymphoma) and
`autoimmune
`conditions
`(rheumatoid arthritis
`and
`others). Rituximab’s impressive efficacy in relapsing
`remitting MS was demonstrated in HERMES,
`a randomized clinical trial,36 and confirmed in 2 other
`trials,37,38 numerous observational studies,e8,e9 and the
`authors’ personal experience.e10 A recent Swedish study
`comparing fingolimod vs rituximab in patients with
`relapsing MS who switched from natalizumab because
`of JC virus antibody positivity showed superiority of
`rituximab over
`fingolimod regarding both efficacy
`(relapses
`in 1.8% of
`rituximab treated patients vs
`17.6% on fingolimod; hazard ratio of 0.10) and safety
`(5.3% adverse event rate in rituximab patients vs 21.1%
`for
`fingolimod; hazard ratio of 0.25 in favor of
`rituximab).39
`At the Rocky Mountain MS Center at the Univer
`sity of Colorado, we infuse rituximab 1,000 mg once
`and repeat with 500 mg IV every 6 months thereafter
`(unless there is reconstitution of CD20 cells, in which
`case we use 1,000 mg every 6 months). While costs
`vary by location and may change over time, the cur
`rent cost for 1,500 mg spread over 2 doses, including
`the infusions themselves, is approximately $20,000 at
`a Walgreen’s infusion center in Colorado near our
`
`institution, well below the average wholesale prices,
`or wholesale acquisition costs of the standard DMTs.2
`It should also be noted that the above dosing strategy
`utilizes 50% or less of rituximab compared to the
`standard rheumatoid arthritis dosing of this drug
`(1 g 4 times a year).
`A partially humanized version of rituximab, ocreli
`zumab, completed 4 phase II and III trials for relapsing
`and primary progressive MS. The 2 phase III trials of
`ocrelizumab in relapsing MS were reported at the
`2015 ECTRIMS (European Committee for Treat
`ment and Research in Multiple Sclerosis) meeting,
`and showed 46% reductions in annualized relapse rates
`and 95% reductions in new enhancing lesions in com
`parison to thrice weekly interferon beta 1a.e11 The
`placebo controlled trial of ocrelizumab for primary
`progressive MS became the first primary progressive
`MS trial to meet its primary endpoint in reducing
`disability.e12 Its predecessor, a 2 year trial of rituximab
`vs placebo in primary progressive MS, was overall neg
`ative, but participants younger than 51 years and with
`enhancing lesions on their baseline brain MRI had
`a significant reduction in likelihood of sustained dis
`ease progression.e13 Ocrelizumab’s maker has filed for
`FDA and other regulatory approvals for relapsing and
`progressive forms of MS in 2016 and is expected to
`receive a decision by January 2017. In our view, ritux
`imab has 2 important advantages over ocrelizumab in
`relapsing MS: an established long term safety record
`(an estimated 312,000 patients with rheumatoid
`arthritis alone were treated with rituximab since its
`approval in 1997 [Genentech, data on file]), and a con
`siderably lower projected price. Counting a phase II
`trial of another anti CD20 monoclonal antibody, the
`completely humanized ofatumumab,e14 there are now
`8 successful phase II and III studies supporting the use
`of anti B cell therapy in MS. The time has come for
`insurance companies to routinely approve payment for
`the highly efficacious anti CD20 monoclonal antibody
`therapy in MS, presently as rituximab.
`While rituximab has the most evidence in support
`of off label use in MS, other agents merit mention as
`well. Leflunomide is a readily available and inexpen
`sive generic drug. Upon ingestion,
`leflunomide is
`almost entirely converted into teriflunomide, a mod
`erately effective FDA approved agent for relapsing
`remitting MS.e15 As such, leflunomide has been used
`off label for MS, although, to our knowledge, no
`studies of this drug in MS have been published.
`Monthly cost of leflunomide ranges from $24.85 to
`$65.68 (GoodRx.com), well below the cost of teri
`flunomide marketed as Aubagio (Sanofi Genzyme,
`Cambridge, MA). A head to head comparison of le
`flunomide with teriflunomide would be instructive.
`Other oral generic immunosuppressants, such as aza
`thioprinee16 and methotrexate,e17 have a long history
`
`1620
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`Page 4 of 6
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`

`in MS, but are regarded as much less efficacious for
`relapse prevention as the newer agents, such as nata
`lizumab or rituximab.
`
`5. Should DMTs be continued indefinitely? The question
`posed in the section title cannot be answered at present.
`All clinical trials that led to FDA approval of DMTs for
`relapsing MS typically had an age cutoff of 55 years or
`younger. Studies in progressive MS, often including
`those up to age 60 or 65, have generally been negative,
`unless one looks at subanalyses by age or recent inflam
`matory disease activity (relapses or enhancing lesions).
`The subanalyses show that younger patients with recent
`active inflammation do appear to benefit, regardless of
`placement into a “relapsing” or “progressive” phenotype
`category.e13,e18 Thus, while it is clear that younger pa
`tients with recent inflammatory disease activity benefit
`from presently available DMTs, it is not clear whether
`the same is true in older patients without recent inflam
`matory activity.
`Discontinuation of interferon beta 1ae19,e20 or na
`talizumab32,33 in patients with highly active disease
`before therapy leads to disease reactivation within
`months of stoppage. But in older patients, who are
`at lower risk of relapsese21 and new enhancing le
`sions,e22 or in patients with no relapses or inflamma
`tory MRI activity for prolonged periods, the benefits
`of continuing relapse suppressive therapies are uncer
`tain. A recent observational study compared the risk
`of relapse and disease progression among patients
`with no relapses for 5 years or more, some of whom
`stopped DMT and others who continued on DMT.40
`The 2 groups were propensity score matched from
`a large MS database, MSBase. Their average age was
`45 years. No difference in relapse rate was observed
`between the 2 groups, suggesting that stopping DMT
`in a nonrelapsing patient in this context does not
`increase risk of subsequent relapses. However, disabil
`ity progression rates were higher among patients who
`stopped DMT. This difference was largely attribut
`able to faster rate of progression among a subset of
`stoppers with no prebaseline disease progression com
`pared to stayers with no prebaseline disease progres
`sion. Thus, it is unknown whether continuation of
`DMT in the older, nonrelapsing patients is war
`ranted. The uncertainty provides justification, per
`haps even an imperative, to conduct a randomized
`discontinuation trial,e23 in which some patients are
`randomized to continue on treatment and others to
`stop therapy. Such trials have been successfully con
`ducted in oncology,e24 rheumatoid arthritise25 and
`other fields, but not in MS. We have recently received
`funding to conduct a randomized discontinuation
`trial in MS.e26 The 2 year, multicenter trial is sched
`uled to open enrollment in early 2017 for 300 pa
`tients who are 55 and older and have had no relapses
`
`or new MRI activity for at least 5 years while main
`tained on DMT. The results of the trial should help
`patients and clinicians make an informed decision as
`to whether and when it may be safe to stop DMT.
`
`CONCLUSIONS Clinical trial agendas in MS are, to
`a large extent, set by the pharmaceutical industry. In
`this article, we argue for greater clinician involve
`ment in shaping the clinical research agenda for
`our field, with special emphasis on developing, and
`bringing to mainstream clinical practice, strategies
`that may decrease costs while enhancing the quality
`of care. We identified a number of possible therapeu
`tic strategies that make medical and economic sense,
`including
`alternative dosing of FDA approved
`DMTs; off label use of highly effective relapse
`suppressants; customizing treatment of
`relapses;
`performing a randomized DMT discontinuation
`trial; and improving specificity of MRI criteria for
`MS and development of alternative biomarkers to
`enhance diagnostic accuracy (table). Some of these
`strategies do not, as yet, have sufficiently high level of
`evidence, and we advocate for high quality research
`that would put these cost effective approaches on
`a firm empiric basis.
`
`AUTHOR CONTRIBUTIONS
`Ilya Kister: study concept and design, drafting of the manuscript, critical revi-
`sion of the manuscript for important intellectual content, study supervision.
`John R. Corboy: study concept and design, drafting of the manuscript, critical
`revision of the manuscript for important intellectual content, study supervision.
`
`STUDY FUNDING
`No targeted funding reported.
`
`DISCLOSURE
`I. Kister served on scientific advisory board for Biogen Idec and Genen-
`tech, and received research support
`from Guthy-Jackson Charitable
`Foundation, National Multiple Sclerosis Society (NMSS), Biogen Idec,
`Serono, Genzyme, and Novartis. J. Corboy served as principal investiga-
`tor on trials sponsored by Sun Pharma and NMSS, received research
`grants from NMSS, DioGenix, PCORI, served as consultant to Novartis,
`Genentech, and Teva Neuroscience, received honoraria from PRIME
`CME and medico-legal work, and serves as Editor of Neurology® Clinical
`Practice. Go to Neurology.org for full disclosures.
`
`Received February 26, 2016. Accepted in final form May 11, 2016.
`
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`1621
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