`
`CNS drugs.
`vy, 29, no. 1 (2015 )
`General Collection
`w1 CN13
`2015-10-21 12:44:08
`
`
`
`DRUG THERAPY IN NEUROLOGY ANDPSYCHIATRY
`
`ETHa UmaCe)
`GSK-3 and Cognitive Dysfunction in Neuropsychiatric Disorders
`
`BipNMle aeCodta
`Emergency and Critical Care Managementof Acute Ischaemic Stroke
`
`Systematic Review
`_ Impact of Medication on Health-Related Quality of Life in GAD
`anMe.2
`Review Articles
`Post-Injection Delirium/Sedation Syndrome with Olanzapine Pamoate
`4 peeeee| Adherencein : with Parkinson’s Disease
`Ee Outpatient Pharmacotherapy
`and Modes ofAdministration for ARS
`ee
`=
`erie ae
`2
`earchArticle
`r
`Cost Effectiveness of Fingolimod, BUetNitinccc Dimethyl Fumarate
`Eoorom Osetuntetcoa Occtage he
`
`4
`
`M
`
`NATIONAL
`LIBRARY OF
`
`Page 1 of 14
`
`Biogen Exhibit 2208
`Mylanv. Biogen
`IPR 2018-01403
`
`
`PENGAD800-631-6989
`
`
` sible PIGINE
`
`[2k-ade OlN0z,
`
`DEPOSITION
`EXHIBIT
`
`Page 1 of 14
`
`Biogen Exhibit 2208
`Mylan v. Biogen
`IPR 2018-01403
`
`
`
`CNS Dru
`
`S
`
`The Americas (North, South, Central
`America and the Caribbean)
`Springer Journal Fulfillment
`233 Spring Street, New York
`NY 10013-1578, USA
`Tel.: 800-SPRINGER(777-4643);
`212-460-1500 (outside North America)
`journals-ny@springer.com,
`servicio-ny@springer.com
`(Central and South America)
`
`Outside the Americas
`Springer CustomerService Center GmbH
`Haberstr. 7, 69126 Heidelberg, Germany
`Tel.: +49-622 1-345-4303
`subscriptions@springer.com
`
`Advertisements
`E-mail contact: advertising@springer.com
`or anzeigen@springer.com
`
`Disclaimer
`Springer publishes advertisernents
`in this journalin reliance upon the
`responsibility of the advertiser to comply
`with all legal requirementsrelating to the
`marketing and sale of products orservices
`advertised. Springer and the editors are
`not responsible for claims made in the
`advertisements published in the journal.
`The appearance of advertisements in
`Springer publications does not constitute
`endorsement, implied or intended, of the
`product advertised or the claims made for
`it by the advertiser,
`
`Office of Publication
`Springer International Publishing AG, °
`GewerbestraBe [1, 6330 Cham, Switzerland
`Springer International Publishing is part of
`Springer Science+Business Media
`
`Editorial Staff
`Editorial Director: Diana Faulds
`Editorial Assistant: Carole Pearson
`
`errors or omissions that may have been
`made. The publisher makes no warranty,
`express or implied, with respect to the
`material contained hercin.
`All articles published in this journal
`are protected by copyright, which covers
`the exclusive rights to reproduce and
`distribute the article (e.g., as offprints),
`as well asall translation rights. No
`material published in this journal may
`be reproduced photographically or
`stored on microfilm, in electronic data
`bases, on videodisks, etc., without first
`obtaining written permission from
`the publisher (respective the copyright
`ownerif other than Springer). The use of
`general descriptive names, trade names,
`trademarks, etc., in this publication, even
`if not specifically identified, docs not
`imply that these namesare not protected
`by the relevant laws and regulations.
`Springer has partnered with Copyright
`Clearance Center’s RightsLink service
`to offer a variety of options for reusing
`Springer content. For permission to reuse
`our content please locate the material that
`you wish to use on link.springer.com or
`on springerimages.com andclick on the
`permissions link or go to copyright.com
`and enterthetitle of the publication that
`you wishto use. Forassistance in placing
`a permission request, Copyright Clearance
`Center canbe contacted directly via
`phone: +1-855-239-3415, fax: +1-978-646-
`8600 or e-mail: info@copyright.com.
`© Springer International Publishing
`Switzerland 2015
`
`Journal Website
`www.springer.com/40263
`Electronic edition: link.springer.com/
`journal/40263
`
`_ Subscription Information
`CNS Drugs is published 12 times a year.
`Volume 29 (12 issues) will be published
`in 2015,
`
`ISSN: 1172-7047 print
`ISSN: 1179-1934 electronic
`
`Forinformation on subscription rates please
`contact Springer Customer Service Center:
`
`Aims and Scope
`CNS Drugs promotes rational
`pharmacotherapy and effective patient
`management within the disciplines of
`clinical psychiatry and neurology by
`providing a regular programmeof review
`articles covering important issues in
`the drug treatment of psychiatric and
`neurological disorders.
`
`The journal includes:
`
`* Leading/currentopinion articles providing
`an overview ofcontentious or emerging
`issues,
`Definitive reviews on approachesto
`the managementofneurological and
`psychiatricillnesses.
`Therapy in Practice reviews providing
`practical recommendationsforspecific
`- clinical situations.
`Adis Drug Evaluations reviewing the
`properties andplace in therapy of both
`newerand established drugs in neurology
`and psychiatry.
`Original researcharticles will also be
`considered for publication.
`
`All manuscripts are subject to peer
`review by international experts. Letters
`to the Editor are welcomed andwill be
`considered for publication.
`
`_ Copyright Information
`ForAuthors
`As soon as anarticle is accepted for
`publication, authors will be requested
`to assign copyright of the article
`(or to grant exclusive publication and
`dissemination rights) to the publisher
`(respective the ownerif other than
`Springer). This will ensure the widest
`possible protection and dissemination of
`information under copyright laws.
`More information aboutcopyright
`regulations for this journal is available at
`www.springer.com/40263
`ForReaders
`
`While the advice and information in this
`journalis believed to be true and accurate
`at the date ofits publication, neitherthe
`authors,the editors, nor the publisher can
`accept any legal responsibility for any
`
`A Adis
`
`Page 2 of 14
`
`Page 2 of 14
`
`
`
`CNS Drugs
`
`Volume 29 - Number1
`
`* 2015
`
`LEADING ARTICLE
`
`Glycogen Synthase Kinase-3 as a Therapeutic Target for Cognitive Dysfunction
`in Neuropsychiatric Disorders
`O, O'Leary - Y. Nolan
`
`THERAPY IN PRACTICE
`
`17
`
`Emergency and Critical Care Managementof Acute Ischaemic Stroke
`S.A. Figueroa « W. Zhao - V. Aiyagari
`
`SYSTEMATIC REVIEW
`
`29
`
`The Impact of Medication on Health-Related Quality of Life in Patients
`with Generalized Anxiety Disorder
`H. Wilson - S. Mannix - H. Oko-osi - D.A. Revicki
`
`41
`
`47
`
`55
`
`71
`
`REVIEW ARTICLES
`
`Post-Injection Delirium/Sedation Syndromein Patients Treated
`with Olanzapine Pamoate: Mechanism,Incidence, and Management
`D. Luedecke - D. Schéttle - A. Karow - M. Lambert - D. Naber
`
`Medication Adherence in Patients with Parkinson’s Disease
`N. Malek - D.G. Grosset
`
`Outpatient Pharmacotherapy and Modesof Administration
`for Acute Repetitive and Prolonged Seizures
`H.R. McKee - B. Abou-Khalil
`
`ORIGINAL RESEARCH ARTICLE
`
`;
`Cost Effectiveness of Fingolimod,Teriflunomide, Dimethyl Fumarate
`and IntramuscularInterferon-B,, in Relapsing-Remitting Multiple Sclerosis
`X. Zhang - J.W. Hay - X. Niu
`
`Further articles can be found at link.springer.com
`
`Indexed in MEDLINE, EMBASE,International Pharmaceutical Abstracts (1PA), BIOSIS Previews,
`BIOSIS Reviews Reports and Meetings, Current Contents/Clinical Medicine, Current Contents/Life
`Sciences, SciSearch, Science Citation Index, Journal Citation Reports/Science Edition, PASCAL,
`Chemical Abstracts Service, Sociedad Iberoamericana de Informacién Cientifica (SHC), Neuroscience
`Citation Index, PsycINFO and Journals@Ovid
`
`Instructions for authors for CNS Drugsare available at www.springer.com/40263
`
`Page 3 of 14
`
`This material was copied
`atthe NLM and may be
`Subject US Copyright Laws
`
`‘\ Adis
`
`Page 3 of 14
`
`
`
`This material may be protected by Copyright law (Title 17 U.S. Code)|*
`CNS Drugs (2015) 29:71-81
`DOI 10,1007/s40263-014-0207-x
`
`
`ORIGINAL RESEARCH ARTICLE
`
`Cost Effectiveness of Fingolimod, Teriflunomide,
`Dimethyl Fumarate and Intramuscular Interferon-Bj,
`in Relapsing-Remitting Multiple Sclerosis
`
`Xinke Zhang + Joe] W. Hay + Xiaoli Niu
`
`Published online: 19 October 2014
`© Springer International Publishing Switzerland 2014
`
`than 90 % of the simulations, dimethyl fumarate was the
`optimal therapy across all WTP values.
`Conclusion The three oral therapies were favoredin the cost-
`effectiveness analysis, Of the four DMDs, dimethy] fumarate
`was a dominant therapy to manage RRMS. Apart from dime-
`thy] fumarate,teriflunomide was the most cost-effective ther-
`apy compared with IM JFN-B),, with an ICER of US$7,115.
`
`
`
`‘ify Ruts
`
`This is the first cost-effectiveness analysis in
`relapsing-remitting multiple sclerosis to (1) make
`comprehensive comparisons betweenthe three new oral
`disease-modifying drugs and the established therapy
`intramuscular (IM)interferon (IFN)-(,,, (2) incorporate
`second-line therapy in the model, and (3) presentresults
`in terms of incremental net monetary benefit (INMB)
`
`Dimethyl fumarate dominated all other therapies
`over the range of willingness-to-pay (WTP) values,
`from US$0 to US$180,000. Compared with IM IFN-
`B,,, at a WTP of US$150,000, INMBs were
`estimated at US$36,567, US$49,780, and US$80,61 1
`for fingolimod,teriflunomide, and dimethyl
`fumarate, respectively. The three oral therapies were
`favored in the cost-effectiveness analysis
`
`Abstract
`Objective The aim of the study was to compare the cost
`effectiveness
`of
`fingolimod,
`teriflunomide,
`dimethyl
`fumarate, and intramuscular (JM) interferon (IFN)-B),4 as
`first-line therapies
`in the treatment of patients with
`relapsing-remitting multiple sclerosis (RRMS).
`Methods A Markov model was developed to evaluate the
`cost effectiveness of disease-modifying drugs (DMDs) from
`a USsocietal perspective. The time horizon in the base case
`was 5 years. The primary outcome was incremental net
`monetary benefit (INMB), and the secondary outcome was
`incremental cost-effectiveness ratio (ICER). The base case
`INMBwillingness-to-pay (WTP) threshold was assumedto
`be US$150,000 per quality-adjusted life year (QALY), and
`the costs were in 2012 US dollars. One-way sensitivity
`analyses and probabilistic sensitivity analysis were con-
`ducted to test the robustness of the model results.
`Results Dimethyl fumarate dominated all other therapies
`over the range of WTPs,
`from US$0 to US$180,000.
`Compared with IM IFN-B),, at a WTP of US$150,000,
`INMBs were estimated at US$36,567, US$49,780, and
`US$80,611 for fingolimod,
`teriflunomide, and dimethy!
`fumarate, respectively. The ICER of fingolimod versus
`teriflunomide was US$3,201,672. One-way sensitivity
`analyses demonstrated the model results were sensitive to
`the acquisition costs of DMDs andthe time horizon, but in
`most scenarios, cost-effectiveness rankings remained sta-
`ble. Probabilistic sensitivity analysis showed that for more
`After dimethyl fumarate, teriflanomide was the most
`pieieiaa
`cost-effective therapy compared with IM IFN-6),,
`with an incremental cost-effectiveness ratio of
`US$7,115. When the monthly cost is below
`US$5,132, fingolimod is cost effective compared
`with IM IFN-B),. However, fingolimod is not cost
`effective compared with teriflunomide
`
`X. Zhang - J. W. Hay (24) » X. Niu
`Departmentof Clinical Pharmacy and Pharmaceutical
`Economics and Policy, Leonard D. Schaeffer Center for Health
`Policy and Economics, University of Southern California,
`University Park Campus, VPD 214-L, Los Angeles,
`CA 90089-3333, USA
`e-mail: jhay @usc.edu
`
`Page 4 of 14
`
`This material was copied
`at the NLM and maybe
`Subject US Copyright Laws
`
`/\ Adis
`
`Page 4 of 14
`
`
`
`72.
`X, Zhang et al.i
`
`1 Introduction
`
`Before the introduction of oral fingolimod (Gilenya™,
`Novartis, East Hanover, NJ, USA), over half of the patients
`with relapsing-remitting multiple sclerosis (RRMS) who
`were treated with disease-modifying drugs (DMDs) were
`using injected interferons (IFNs) [1], and intramuscular
`(IM) IFN-8;, (Avonex™, Biogen Idec, Weston, MA, USA)
`had the largest market share in 2010 [2]. However, IM
`IFN-B;, and other traditional DMDs require long-term
`parenteral administration, which imposes a burden on
`patients and may have a significant impact on medication
`adherence. Over the past few years, three new oral DMDs,
`namely fingolimod,
`teriflunomide
`(Aubagio”, Sanofi
`Aventis, Cambridge, MA, USA), and dimethyl fumarate
`(Tecfidera”, Biogen Idec, Weston, MA, USA), were
`approved by the FDA in 2010, 2012, and 2013, respec-
`tively. Fingolimod wasthefirst oral therapy approved, and
`the Trial Assessing Injectable Interferon versus FTY720
`Oral in Relapsing-Remitting Multiple Sclerosis (TRANS-
`FORMS) showed that fingolimod appeared to be more
`effective than IM IFN-B,,
`in reducing the frequency of
`relapses [3]. The large-scale phase II clinical
`trials the
`Teriflunomide Multiple Sclerosis Oral (TEMSO)trial and
`the Determination of the Efficacy and Safety of Oral
`Fumarate in Relapsing-Remitting MS (DEFINE)trial also
`demonstrated that
`teriflunomide and dimethyl
`fumarate,
`respectively, significantly reduced annualized relapserates,
`slowed disability progression, and reduced the number of
`lesions on magnetic resonance imaging [4, 5]. Although
`these new oral.therapies were thought to contribute to the
`growth of the total costs of multiple sclerosis (MS), so far
`there is no comprehensive evidence on either the cost
`effectiveness of the new oral DMDs compared with the
`established treatment
`IM IFN-f,,, or
`incremental cost
`effectiveness among the oral therapies. For these reasons,
`this paper compares the cost effectiveness of fingolimod,
`teriflunomide, dimethyl fumarate, and IM IFN-[,, asfirst-
`line therapies in the treatment of patients diagnosed with
`RRMS.
`
`2 Materials and Methods
`
`2.1 Model Overview
`
`The cost-effectiveness analysis was conducted from a US
`societal perspective over a 5-year time horizon. We chose
`5-year rather than 10-year orlife time as the time horizon
`because (1) extrapolating a I- or 2-year randomized con-
`trolled trial (RCT) over long time horizons requires more
`unreliable assumptions on model extrapolations [6] and (2)
`high discontinuation rates imply that a large proportion of
`patients will discontinue or develop secondary-progressive
`multiple sclerosis (SPMS) over time [3-5, 7]. Costs were
`reported in 2012 US dollars, and both costs and outcomes
`were discounted at a 3 % annual rate in the base case
`scenario. The primary outcome was incremental net mon-
`etary benefit (INMB), and the secondary outcome was
`incremental cost-effectiveness ratios (ICERs). INMB was
`chosen as the primary outcome since, when comparing
`multiple treatment options,
`it more clearly delineates
`treatments with dominance or extended dominance[8, 9].
`The willingness-to-pay (WTP) threshold was assumed to
`be US$150,000 per quality-adjusted life year (QALY),
`whichis three times the 2012 US gross domestic product
`(GDP) per capita, as recommended by the World Health
`Organization {10, 11]. The choice of US$150,000 as the
`WTPthresholdrather than the antiquated US$50,000 value
`in the US context is also supported by the study of Brai-
`thwaite etal, [12] and is used in numerous previous studies
`[13-16].
`A Markov model was developed in Microsoft® Excel to
`simulate the disease progression of patients with RRMS
`(Fig. 1). The cycle is { month, The comparators included
`oral fingolimod at a daily dose of 0.5 mg, oral terifluno-
`mide 14 mg once daily, oral dimethyl fumarate 120 mg
`twice a day for the first 7 days and 240 mg twice a day
`after 7 days, and IM IFN-[,, at a weekly dose of 30 pg
`[17]. The disease progression was modeled by the Expan-
`ded Disability Status Scale (EDSS), which is most widely
`used in the measurement of MS [18]. Specifically, health
`
`Fig, 1 Markov model for the
`disease progression of multiple
`sclerosis. EDSS Expanded
`Disability Status Scale
`
`
`
`EDSS 0.0-2.5
`Relapse
`
`EDSS 3,0-5.5
`Relapse
`
`
`
`
`Fy
`
`«>
`
`QY
`
`
`
`EDSS 10.0
`(Death)
`
`All health states may
`progress to death
`
`LN Adis
`
`Page 5 of 14
`
`This material was copied
`at the NLM and maybe
`Subject US Copyright Laws
`
`Page 5 of 14
`
`
`
`73
`Cost Effectiveness of Oral Disease-Modifying Drugs Versus IM IFN-Bj).
`
`states were divided as EDSS 0.0-2.5 (no or mild disabil-
`ity), EDSS 3.0-5.5 (moderate disability, ambulatory with-
`out aid), EDSS 6.0-7.5 (waking aid required), EDSS
`8.0-9.5 (restricted to bed), EDSS 10.0 (death) and another
`two relapse states. Since MS is a progressive disease,
`patients were assumedto only progress to a more severe
`health state ora relapsestate.
`A cohort of 1,000 patients was assumed to enter the
`model, Consistent with the clinical trials, all patients were
`initially distributed to EDSS 0.0-2.5 and 3.0-5.5 states and
`treated withfirst-line DMDs [3-5]. The EDSS distribution
`ratio between the two states was estimated from a national
`cross-sectional survey [19]. In any cycle during the simu-
`lation, patients could discontinue the drug and then tran-
`sition to a second-line treatment, natalizumab, or to the
`symptom management
`(SM) arm without active drug
`therapy. Moreover, patients could also discontinue natal-
`izumab due to insufficient response or adverse events and
`then switch to SM treatment.
`The decision to choose natalizumab as the second-line
`therapy was based on the fact that (1) natalizamab was
`specifically indicated for use when previous DMDsfailed,
`as recommended by American Academy of Neurology
`[20]; (2) a retrospective cohort study found that approxi-
`mately 10 % of patients who were initially treated with
`IFN-B or glatiramer acetate (GA) experienced break-
`through disease and either switched to natalizumab or an
`immunosuppressant (e.g., mitoxantrone) or declined new
`therapy [21] (however, according to another study, which
`followed a cohort from 2000 to 2008, only 1 % of the first-
`line and second-line DMD populations used mitoxantrone
`[22]); and (3) otherfirst-line drugs are often used as sec-
`ond-line therapies, despite not being indicated after failure
`of a previous DMD, and they are actually similar in
`
`efficacy; however, there is evidence that switching to na-
`talizumab is more effective than switching to other first-
`line drugs
`[23]. Therefore, patients were assumed to
`receive natalizumab as second-line therapy.
`Patients in EDSS 0.0-2.5 and 3.0-5.5 states would
`likely transition to a temporary state of relapse and stay for
`a cycle (1 month). Following a relapse, patients could
`transition back to the previous state or progress to a next
`more severe health state. According to a recent natural
`history study of SPMS, for patients initially diagnosed with
`RRMS, 80.0 % reached SPMS at or before EDSS 6.0 and
`99,5 % at or before EDSS 8.0 [24]. Thatis to say, for those
`transitioned to EDSS 6.0, at
`least 80 % of the patients
`would have already reached SPMS, and so would almost
`all of the patients who progressed to EDSS 8.0. Therefore,
`it was assumed that patients in EDSS 6.0-7.5 and EDSS
`8.0-9.5 had developed SPMS and thus were not associated
`with further relapses. Since these DMDsare indicated for
`relapse forms of MS,patients transitioned to EDSS 6.0-7.5
`and EDSS 8.0-9.5 would stop DMD treatment and then be
`treated with SM.
`The model design in this paper was consistent with
`previous cost-effectiveness studies comparing DMDs in
`that the same health states were classified and the same
`disease progression path was defined [2, 25-27]. The health
`states were decided in a way that
`the transition points
`(EDSS 3.0, 6.0, 8.0, and 10) reflected key disability levels
`in the natural history of MS and are critical in defining
`clinical course [7, 28-30]. In our model, we also allowed
`the patients to switch to second-line DMD treatment when
`they discontinued the first-line therapy,
`to better reflect
`clinical practice [20, 31]. In addition, we had each author
`verify the model equations and computations indepen-
`dently to ensure the internal validity [32].
`
`Table 1 Baseline characteristics of the patients
`Variable
`FREEDOMS[33]
`
`TRANSFORMS [3] °
`
`TEMSO[4]
`
`DEFINE [5]
`
`Placebo
`
`FIN
`
`FIN
`
`IM IFN-B),
`
`TER
`
`DF
`
`i D
`
`emographic characteristics
`Age, years
`Mean + SD
`Median(range)
`Female sex, %
`White race, %
`Clinical characteristics
`
`37.2 + 8.6
`37.0 (18-55)
`71.30
`~
`
`36.6 + 8.8
`36.0 (18-55)
`69.60
`-
`
`36.7 +88
`
`37 (18-55)
`65.40
`93.70
`
`36.0 + 8.3
`
`36 (18-55)
`67.80
`93.80
`
`37.8 + 82
`
`38.1491
`
`es
`71
`96.90
`
`i
`72
`78
`
`Relapses, No.
`In previous year, mean + SD
`In previous 2 years, mean + SD
`EDSSscore, mean + SD
`
`1440.7
`22412
`25 +13
`
`1.5 + 0.8
`2] ck Tel
`2.34 1.3
`
`15412
`#5 438
`
`1540.8
`23412
`
`13407
`2241.0
`
`13407
`=
`
`2.244133
`
`2194126
`
`2674124
`
`24041.29
`
`DFdimethyl fumarate, EDSS Expanded Disability Status Scale, FIN fingolimod, /FN interferon, /M intramuscular, TER teriflunomide
`
`Page 6 of 14
`
`This material was copied
`atthe NLM end may be
`Subject US Copyright Laws
`
`4N Adis
`
`Page 6 of 14
`
`
`
`74
`X. Zhang et al.
`
`2.2 Patient Characteristics
`
`The baseline characteristics of the modeled patients were
`very similar in the phase III clinical trials across the four
`DMDs
`(Table 1)
`[3-5, 33]. Generally, patients were
`between 18 and 55 years old, had a diagnosis of RRMS,
`had had at least two relapses during the previous 2 years or
`at least one relapse during the previous year before ran-
`domization, and had an EDSS score of 0-5.5. Based on a
`national survey study,
`the initial proportions ofpatients
`distributed in EDSS 0.0-2.5 and EDSS 3.0-5.5 were esti-
`mated at 41.3 and 58.7 %, respectively [19],
`
`2.3 Transition Probabilities
`
`Transition probabilities for disease progression, relapses,
`- and discontinuation were obtained from the literature and
`modeled using the DEALE method (Table 2) [3-5, 33-
`36]. For patients in SM,
`the EDSS progression proba-
`bilities were estimated from the London Ontario natural
`history study of MS [7]. The London Ontario data were
`used because, unlike in other studies, the patients in the
`study did not receive disease-modifying therapies and the
`database was subjected to a rigorous quality review in
`2009 [37]. There were 806 RRMS-onset patients in the
`database, and the shortest follow-up was 16 years. Since
`the patients were similar in demographics and clinical
`characteristics, for patients treated with fingolimod,
`teri-
`flunomide, dimethyl
`fumarate,
`and natalizumab,
`the
`hazard ratios of disease progression for DMDs compared
`with placebo reported in phase III placebo-controlled
`trials were used to derive the I-month transition proba-
`bilities for each DMD. For the IFN-},, arm,
`the hazard
`ratio from the head-to-head trial TRANSFORMS between
`fingolimod and IFN-B,, was also used to estimate tran-
`sition probabilities [3].
`The transition probabilities of relapses for patients in
`SM were obtained from the placebogroup in the FT'Y720
`Research Evaluating Effects of Daily Oral Therapy in
`Multiple Sclerosis (FREEDOMS)trial [33]. Hazard ratios
`of
`relapses between DMDs
`(teriflunomide, dimethyl
`fumarate, and natalizumab) and placebo were used to
`derive the transition probabilities to relapse state for the
`DMDs.Forpatients treated with fingolimod and IFN-f),,
`relapse probabilities were estimated by using the data in the
`TRANSFORMStrial [3]. All discontinuation rates were
`extracted from the corresponding phaseIII clinical trials.
`After discontinuation of the first-line therapy, the assign-
`mentratio between natalizumab and SM was assumedto be
`equal
`in the base case scenario, and extreme cases were
`tested in sensitivity analyses. Since the mortality rate due
`to MSis very low,survival probabilities were based on the
`mortality rates of the general population [38]. The age-
`
`specific mortality rates were estimated from the life
`expectancy data in national vital statistics reports using the
`DEALE method [35, 36, 39].
`
`2.4 Utilities
`
`Since utilities were not available in the pivotal RCTs, we
`reviewed the literature and identified the best available
`evidence to support the utility estimates. The utilities for
`each health state from EDSS 0.0 to EDSS 9.5 and the
`disutility for IFN-8;, were obtained from the Prosseretal.
`[40] quality-of-life study. The study used the standard-
`gamble method to measure patient and community pref-
`erences for treatments and health states in patients with
`RRMS. The Prosser et al.
`[41] study was used because
`standard-gamble was thought to be the gold standard in
`preferenceelicitation since it is the only method thatesti-
`mates Von-Neumann—-Morgenstern
`utility
`(preference
`measured under uncertainty) [41]. Also, since this study
`was performed from a societal perspective, use of com-
`munity preferences was more appropriateasit reflected the
`society’s preference on the resource allocation [42]. Dis-
`utility for relapses was based on the Kobelt et al. study
`[19]. For the effects of fingolimod and natalizumab, though
`there was evidencethat fingolimod and natalizumab could
`improve the quality of life of MS patients significantly [43-
`45], no study on utility impacts was available. Therefore, to
`be conservative,
`the disutility for fingolimod and natal-
`izumab was assumed to be 0 in the base case scenario.
`Changes in assumed base case utility were explored in
`sensitivity analyses. For
`teriflunomide, one study has
`demonstrated that there was no disutility associated with
`administration of teriflunomide, so the impact of teriflun-
`omide on utility was assumed to be 0in the base case
`analysis [46]. Dimethyl fumarate has been reported to have
`significant improvements in physical and mental aspects of
`health and functioning, where the change in EQ-5SD value
`was 0.01 (47, 48]. The base case utilities and the effects of
`DMDson utilities are shown in Table 2.
`
`2.5 Costs
`
`Costs in the model were mainly obtained from the cost-of-
`illness study by Kobelt et al,
`[19] and inflated to 2012
`dollars (Table 2). We applied the results from the Kobelt
`et al. [19] study because the costs were reported on the
`basis ofstratified EDSS score, which corresponded to each
`health state in our model. The costs included costs of
`hospital
`inpatient care, ambulatory care,
`tests, drugs
`(DMDsand other drugs), services, adaptations and costs of
`informal care. The productivity losses were not included,
`because the costs associated with productivity were cap-
`tured in the QALYs [49]. All drug costs were obtained
`
`4 Adis
`
`——
`
`Page 7 of 14
`
`This material was copied
`atthe NLM and maybe
`Subject US Copyright Laws
`
`Page 7 of 14
`
`
`
`Cost Effectiveness of Oral Disease-Modifying Drugs Versus IM IFN-B,, 7seeereea
`
`
`Table 2 Parameters and range
`;
`One-way SA range”
`Base case
`Parameters
`.
`ahs
`-
`
`
`
`
`in one-way sensitivity analysis ayS/\Tang SourcesneUTTEInTTIASIRErae :
`IEEEeno
`Monthly probability of disease progression (SM)
`EDSS 0.0-2.5
`EDSS 3.0-5.5
`EDSS 6.0-7.5
`Monthly probability of progressing to death
`EDSS 0.0-2.5
`EDSS 3.0-5.5
`EDSS 6.0-7.5
`EDSS 8.0-9.5
`Annual relapse rate for SM
`Annual relapse rate for FIN
`Annual relapse rate for IM IFN-Bia
`HRof disease progression
`FIN vs, SM
`IM IFN-B), vs. FIN
`TERvs. SM
`DF vs. SM
`NATvs. SM
`HR of annual relapse rate
`TERvs. SM
`DFvs. SM
`NATvs. SM
`Annual discontinuation rate for FIN
`Annual discontinuation rate for IM IFN-B ya
`Discontinuation rate for TER, 2 year
`Discontinuation rate for DF, 2 year
`Discontinuation rate for NAT, 2 year
`Assignmentratio between NAT and SM
`Utilities estimates
`
`0.005760
`0.007194
`0.005760
`
`0.001684
`0.002348
`0.003121
`0.004457
`0.400
`0.160
`0.330
`
`0.700
`1,353
`0,700
`0.620
`0.580
`
`0.720
`0.510
`0.410
`0.103
`0.118
`0.265
`0.310
`0.083
`0.5:0.5
`
`NIA
`
`N/A
`
`N/A
`0.120
`0.248
`
`0.525
`1.015
`0.525
`0,465
`N/A
`
`0.540
`0.383
`N/A
`0.077
`0.089
`0.199
`0.233
`N/A
`0:1
`
`0.200
`0.413
`
`0.875
`1.692
`0.875
`0.775
`
`0.900
`0.638
`
`0.128
`0.148
`0.332
`0.388
`
`1:0
`
`{7]
`17]
`[7]
`
`[39]
`(39)
`(39)
`[39]
`[39]
`(3]
`13)
`
`133}
`[3}
`[4]
`{5]
`[34]
`
`[4]
`[5]
`[34]
`(3]
`[3]
`[4]
`{5]
`134]
`
`0.899
`0.821
`0.769
`0.491
`~0.094
`-O.115
`0
`0
`0.01
`0
`
`0.674
`0.616
`0.577
`0.368
`—0.071
`—0.086
`—0.03
`—0.03
`—0.03
`N/A
`
`i
`J
`0.961
`0.614
`—0.118
`—0,144
`0.03
`0.03
`0.03
`
`[40]
`[40}
`[40]
`[40}
`[19]
`(40)
`[43, 44]
`[46]
`(47, 48}
`145]
`
`Utility EDSS 0,0-0-2,5
`Utility EDSS 3.0-0-5.5
`Utility EDSS 6.0-0-7.5
`Utility EDSS 8,0-0-9.5
`Disutiliry for relapse
`Disutility for IM IFN-By.
`Impact of FIN onutility
`Impact of TER onutility
`Impact of DF on utility
`Impact of NAT onutility
`Monthly costs, 2012 US dollars.
`[50]
`$5,204
`$3,123
`$4,164
`WACfor FIN
`(50)
`$4,794
`$2,876
`$3,835
`WAC for IM IFN-Bi,
`[50}
`$4,150
`$2,490
`$3,320
`WAC for NAT
`{50]
`$4,630
`$2,778
`$3,704
`WACfor TER
`[50]
`$4,182
`$2,509
`$3,346
`WAC for DF
`[19]
`$2,163
`$1,298
`$615
`Cost of EDSS 0.0-2.5
`DF dimethyl fumarate, EDSS
`[19]
`$4,614
`$2,768
`$1,289
`Cost of EDSS 3.0-5.5
`Expanded Disability Status Scale,
`
`
`PIN Solio,HEMaddy sue|OHHCag of DSS 60-75
`NATnatalizumab, SA sensitivity
`Cost of EDSS 8.0-9.5
`$6,369
`$8,093
`$13,489
`[19]
`analysis, SM symptom
`Cost of relapse
`$5,008
`$3,756
`$6,259
`[5]
`management, TER teriflunomide,
`DigeoUNE Tate
`0.03
`0
`0.05
`WAC wholesale average cost
`o! aepe' oy annenaindieaied
`Time horizon
`5 years
`2 years
`10 years
`
`Page 8 of 14
`
`This material wes copied
`atthe NLM and may be
`Subject US Copyright Laws
`
`4 Adis
`
`Page 8 of 14
`
`
`
`from the Federal Supply Schedule drug prices [50]. Costs
`of relapses were estimated from a cross-sectional, web-
`based survey that investigated the impacts of relapses on
`costs and quality oflife for patients with RRMSin the USA
`[51].
`
`X, Zhang et al.
`76
`OOne
`parameter variation resulted in a major change in conclu-
`sion [49]. Tornado diagrams were plottedin the order from
`most sensitive parameter to least sensitive. Moreover,
`sensitivity to time horizon was specifically tested by
`varying the time horizon from 2 to 30 years under both
`discounted and non-discounted scenarios.
`The robustness of the base case results was also tested
`by probabilistic sensitivity analysis based on a second
`order Monte Carlo simulation (1,000 times). Choice of
`the distribution for the model
`inputs was based on the
`recommendations
`and reflected
`how the
`confidence
`interval of each parameter was estimated [52]. The dis-
`tributions of hazard ratios and annual relapse rates were
`assumed to be log-normal [53]. Utilities were assumed to
`follow a beta distribution which is confined between 0
`and 1
`[53]. Health care costs for each health state and
`drug acquisition costs were assumed to follow a gamma
`distribution [53]. The result of the probabilistic sensitivity
`analysis was reported as the probability of each drug
`maximizing the net monetary benefits (NMBs) over the
`range of WTPs [54]. That is the probability of each drug
`being the optimal therapy.
`
`2.6 Sensitivity Analysis
`
`One-way sensitivity analyses were conducted to test the
`robustness of the pairwise comparisons of three oral ther-
`apies versus IM IFN-B,, and the robustness of the optimal
`therapy selection by using INMB asthe outcome. The base
`case inputs of the parameters were varied by 25 % in both
`positive and negative directions, unless indicated otherwise
`(Table 2). We varied the parameters by 25 % so that the
`upper and lower bound of the sensitivity analysis range
`differed markedly from the base case inputs. The 25 %
`variation ranges of the parameters were also comparable to
`their corresponding 95 % confidence intervals where
`available. Key parameters that may affect
`the disease
`progression,utilities and costs were included in the ana-
`lysis. In addition, a threshold analysis was conducted if a
`
`Table 3 Results for the base case scenario (WTP = US$150,000)
`DMDs
`Cost
`QALY
`NMB
`INMB vs. IM IFN-B
`
`ICER vs, IM IFN-B 1.
`
`ICER:FIN vs. TER
`
`a I
`
`M IFN-B i,
`$223,606
`3.34
`$276,745
`=
`a
`_
`TER
`$226,085
`3,68
`$326,525
`$49,780
`$7,115
`_
`FIN
`$239,947
`3.69
`$313,312
`$36,567
`$46,328
`$3,201,672
`DF
`$200,145
`3.72
`$357,356
`$80,611
`Dominant
`_
`DFdimethyl fumarate, DMDs disease-modifying drugs, FIN fingolimod, /CER incremental cost-effectiveness ratio, /FN interferon, IM intra-
`muscular,
`/VMB incremental net monetary benefit, NMB net monetary benefit, QALY quality-adjusted life year, TER teriflunomide, WTP
`willingness to pay
`
`Fig. 2 Net monetary benefits of
`the disease-modilying drugs.
`IFN interferon,
`JM intramuscular
`
`500000
`
`400000
`
`300000
`
`200000
`
`100000
`
`
`
`Netmonetarybenefits -100000
`
`
` 80000
`
`140000
`
`160000
`
`180000
`
`100000
`
`
`120000
`
`-200000
`
`-300000
`
`
`
`Dimethyl fumarate
`
`cc Teriflunomide
`
`seceeees Fingolimod —.— IMIFN B-1a
`
`Willingness-to-pay
`
`/N Adis
`
`Page 9 of 14
`
`This material was copied
`atthe NLM and maybe
`Subject US Copyright Laws
`
`Page 9 of 14
`
`
`
`Cost Effectiveness of Oral Disease-Modilying Drugs Versus IM IFN-B 4
`77
`
`Fig. 3. Results for one-way
`sensilivily analysis. DF
`dimethyl fumarate, EDSS
`Expanded Disability Status
`Scale, FIN fingolimod, //°N
`interferon, /M intramuscular,
`NAT natalizumab, SM symptom
`management, TER
`teriflunomide, WAC wholesale
`average cost, yr years
`
`(a) Fingolimod vs. IM IFN B-1a
`Monthly WAC for FIN
`Monthly WACfor IM IFN B-1a
`Time horizon
`Impactof FIN onutility
`Disutility for IM IFN B-1a
`;
`oo
`Annualdiscontinuation rate for IM IFN B-1a
`Annual discontinuation rate for FIN
`Utility EDSS 6.0-0-7.5
`Discount rate
`
`——S
`peor
`cnrecreens
`=—
`SI
`Ea
`ge
`
`Assignmentratio between NAT and SM
`-$10,000
`
`a
`$70,000
`$50,000
`$30,000
`$10,000
`Incremental net monetary benefit
`
`$