CNS drugs-
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`DRUG THERAPYIN NEUROLOGYAND PS YCHIATRY
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`Leading Article
`GSK—3 and Cognitive Dysfunction in Neuropsychialric Disorders
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`Therapy in Practice
`Emergency and Critical Care Management of Acute Ischaemic Stroke
`
`Systematic Review
`_, Imp3ct of Medication on Health-Related Quality of Life in CAD
`,
`. if;
`33$;
`Review Articles
`
`Post—Injection Delirium/Sedation Syndrome with Olanzapine Pamoate
`__Medicatio€ Adherencqin Pa-enrs with Parkinsons Disease
`Olgpatlcmyacoerapi§3ndModesofAdmiuistmtiontorARS
`Origfl
`earch Article
`
`Cost Effectiveness of Fingo- o,d Teriflunomide, Dimethyi Fumarate
`and Intra nu '
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`

`

`CNSDtugs
`
`Volume 29 - Number 1
`
`' 2015
`
`LEADING ARTICLE
`
`Glycogen Synthase Kinase-3 as a Therapeutic Target for Cognitive Dysfunction
`in Neuropsychiatric Disorders
`0. O’Leary - Y. Nolan
`
`17
`
`29
`
`41
`
`47
`
`55
`
`7]
`
`THERAPY IN PRACTICE
`
`Emergency and Critical Care Management of Acute Ischaemic Stroke
`SA. Figueroa - W. Zhao - V. Aiyagari
`
`SYSTEMATIC REVIEW
`
`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
`
`REVIEW ARTICLES
`
`Post-Injection Delirium/Sedation Syndrome in Patients Treated
`with Olanzapine Pamoate: Mechanism, Incidence, and Management
`D. Luedecke - D. Schijttle - A. Karow - M. Lambert - D. Naber
`
`Medication Adherence in Patients with Parkinson’s Disease
`N. Malek - D.G. Grosset
`
`Outpatient Pharmacotherapy and Modes of Administration
`for Acute Repetitive and Prolonged Seizures
`H.R. McKee - B. Abou-Khalil
`
`ORIGINAL RESEARCH ARTICLE
`
`.
`Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl “Wm-ate
`and Intramuscular Interferon-[5m in Relapsing-Remitting Multiple SCIeFOSlS
`X. Zhang - J.W. Hay - X. Niu
`
`Further articles can be found at link.sptinger.com
`
`Indexed in MEDLINE, EMBASE, International Pizarntacenticcti Abstracts (IPA), 310-575 Previenw.
`BIOSIS Reviews Reports and Meetings, Current Contents/Clinical Medicine, Cnrrcnt Contents/Life
`Sciences, SciSem'clt. Science Citation Index, Journal Citation Reports/Science Edition, PASCAL,
`Chemical Abstracts Service, Sociecictd lberatnnericana dc Ity’ornmcién Cicnttft'c'a (511C). Neuroscience
`Citation Index. Psyc'INFO and Jonrnais@0vid
`
`Instructions for authors for CNS Drugs are available at www.5pringer.com/40263
`
`Fhis material was copied
`at the NLM and may be
`So bject US copyright Laws
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`A Adis
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`Page 3 of 14
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`Page 3 of 14
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`

`

`CNS Drugs (EOIS) 29:71—81
`DOI ll).lilil7‘ls40263-(ll4-0207-X
`
`
`This material may be protected by Copyright law (Title 17 US. Code)
`
`'
`
`ORIGINAL RESEARCH ARTICLE
`
`Cost Effectiveness of Fin-golimod, Teriflunomide,
`Dimethyl Fumarate and Intramuscular Interferon-B13.
`in Relapsing-Remitting Multiple Sclerosis
`
`Xinke Zhang - Joel W. Hay - Xiaoli Niu
`
`Published online:
`
`|9 October 20M
`
`© Springer International Publishing Switzerland 20M
`
`Abstract
`
`Objective The aim of the study was to compare the cost
`effectiveness
`of
`fingolimod,
`terillunomicle,
`dimethyl
`fumarate, and intramuscular (1M) interferon (WIND-[3.“ as
`first—line
`therapies
`in the treatment of patients with
`relapsingqemitting multiple sclerosis (RRMS).
`Methods A Markov model was developed to evaluate the
`cost effectiveness of disease—modifying drugs (DMDs) from
`a US societal 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
`INMB willingness-to—pay (WTP) threshold was assumed to
`be US$150,000 per quality-adjusted life year (QALY), and
`the costs were in 201?. 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 [M IFN-Bm, at a WTP of US$150,000.
`INMBs were estimated at US$36,567, US$49,780, and
`US$80,6]1 for fingolimod,
`terifiunomide, and dimethyl
`fumarate, respectively. The ICER of fingolimod versus
`terillunomide was US$3.201,672. One—way
`sensitivity
`analyses demonstrated the model results were sensitive to
`the acquisition costs of DMDs and the time horizon, but in
`most scenarios, cost-effectiveness rankings remained sta—
`ble. Probabilistic sensitivity analysis showed that for more
`_______—,____________——
`
`X. Zhang - J. W. Hay (53]) - X. Niu
`Department of 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 Angelcs,
`CA 90089-3333. USA
`e-mail: jhay@usc.edu
`
`than 90 % of the simulations, dimethyi fumarate was the
`
`optimal therapy across all WTP values.
`Conclusion The three oral therapies were favored in the cost—
`
`effectiveness analysis. Of the four DMDs, dimethyl fumarate
`was a dominant therapy to manage RRMS. Apart from dime—
`thyl fumarate, terifiunomide was the most cost-effective ther—
`apy compared with IM JPN-Bl“, with an ICER of US$7.115.
`
`
`
`This is the first cost-effectiveness analysis in
`relapsing—remitting multiple sclerosis to (1) make
`comprehensive comparisons between the three new oral
`disease—modifying drugs and the established therapy
`intramuscular (1M) interferon (lFNHSla, (2) incorporate
`second-line therapy in the model, and (3) present results
`in terms of incremental net monetary benefit (INMB)
`
`Dimethy] fumarate dominated all other therapies
`over the range of willingness-to-pay (WTP) values,
`from US$O to US$180,000. Compared with 1M IFN-
`
`Btu, 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
`
`After dimethyl fumarate, terifiunomide was the most
`cost-effective therapy compared with 1M IFN-Bla,
`with an incremental cost—effectiveness ratio of
`
`US$11 15. When the monthly cost is below
`US$5.132, fingolimod is cost effective compared
`with 1M lFN-Blu. However, fingolimod is not cost
`effective compared with teriflunomide
`
`A Adis
`
`Page 4 of 14
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`at the NW and may be
`Su inject LIE. Copyright Laws
`
`Page 4 of 14
`
`

`

`72
`X. Zhang el al.
`—.—.....__.—_—.—_——_-——-—u——-—_-—~—'————-
`
`1 Introduction
`
`Before the introduction of oral fingoiimod (GilenyaTM,
`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 (lFNs) [I], and intramuscular
`([M) Inn-[3,, (Avonexw, Biogen ldec, Weston, MA, USA)
`had the largest market share in 2010 [2]. However, 1M
`IFN-Bm 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,
`teriilunomide
`(Aubagio‘m, 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 was the first 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 1M IFN-Bta in reducing the frequency of
`relapses [3]. The large-scale phase IIi 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
`teritlunomide and dimethyl
`fumarate,
`
`respectively, significantly reduced annualized relapse rates,
`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 1M lFN-Bm, or
`incremental cost
`effectiveness among the oral therapies. For these reasons,
`this paper compares the cost effectiveness of lingolimod,
`teriflunomide, dimethyl furnarate, and 1M lFN-[llu as first-
`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 or life time as the time horizon
`because (1) extrapolating a l- 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 20l2 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 ([NMB), and the secondary outcome was
`incremental cost—effectiveness ratios (lCERs). 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 03:31:30,000 per quality-adjusted life year (QALY).
`which is three times the 2012 US gross domestic product
`(GDP) per capita, as recommended by the World Health
`Organization [10, ii]. The choice of US$15(),000 as the
`WTP threshold rather than the antiquated US$50.000 value
`in the US context is also supported by the study of Brai—
`thwaite et al. [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. l). The cycle is 1 month. The comparators included
`oral iingolimod at a daily dose of 0.5 mg, oral terifluno-
`midc 14mg 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 lFN-B.,, 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
`Disabiiity Status Scale
`
`EDSS 0.0-2.5
`Relapse
`
`
`
`EDSS 3.0-5.5
`Relapse
`
`
`
`
`
`
`EDSS 10.0
`
`(Death)
`
`
`
`A Adis
`
`Page 5 of 14
`
`This material was cupied
`attire NLM and maybe
`Subject: US Copyright Law;
`
`All health states may
`progress to death
`
`Page 5 of 14
`
`

`

`73
`Cost Effectiveness of Oral Disease-Modifying Drugs Versus 1M lFN‘iila
`
`states were divided as EDSS 0.0125 (no or mild disabil-
`ity), EDSS 3.0—5.5 (moderate disability, ambulatory with-
`out aid), EDSS (3.0—7.5
`(waking aid required), EDSS
`8.09.5 (restricted to bed), EDSS 10.0 (death) and another
`two relapse states. Since MS is a progressive disease,
`patients were assumed to only progress to a more severe
`health state or a relapse state.
`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 with first-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) natalizumab was
`specifically indicated for use when previous DMDs failed.
`as recommended by American Academy of Neurology
`120]; (2) a retrospective cohort study found that approxi-
`mately 10 % of patients who were initially treated with
`[FN-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-fine DMD populations used mitoxantrone
`[22]); and (3) other first-line drugs are often used as see-
`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 3055 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]. That is 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—75 and EDSS
`8.0—9.5 had developed SPMS and thus were not associated
`with further relapses. Since these DMDS are indicated for
`relapse forms of MS, patients transitioned to EDSS 6.0-75
`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, 3]]. 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
`
`W V
`
`ariable
`
`FREEDOMS [33]
` TRANSFORMS [3]
`
`'
`
`TEMSO [4]
`
`DEFINE [5]
`
`FIN
`Placebo
`DF
`TER
`IM IFN‘BIa
`FIN
`.—_—_________—________——-—-———'—'—_—v——_
`
`Demographic characteristics
`Age, years
`Mean :1: SD
`
`Median (range)
`Female sex, %
`White race, Va
`Clinical characteristics
`
`37.2 :1: 8.6
`
`36.6 d: 8.8
`
`37.0 (18—55)
`71.30
`—
`
`36.0 (18—55)
`69.60
`—
`
`36.7 a: 8.8
`
`37 (IS-55)
`65.40
`93.70
`
`35.0 :t 8.3
`
`36 (18—55)
`67.80
`93.80
`
`37.8 a: 8.2
`
`38.1 a 9.1
`
`—
`71
`96.90
`
`_
`72
`78
`
`Relapses, No.
`
`1.3 :t 0.7
`1.3 a 0.7
`1.5 :t 0.8
`1.5 :l: 1.2
`1.5 d: 0.8
`1.4 :1: 0.7
`In previous year, mean :1: SD
`_
`2.2 :1: 1.0
`,
`2.3 :1: 1.2
`2.3 :1; 2.2
`2.1 :1: 1.1
`2.2 i 1.2
`In previous 2 years, mean :1: SD
`
`
`
`2.67 a 1.242.19 :1: 1.262.24 a: 1.33 2.40 :1: 1.29
`2.3 :l: 1.3
`2.5 :t 1.3
`EDSS score, mean :t SD
`
`DF dimethyl fumarate. EDSS Expanded Disability Status Scale, FIN fingolimod, IFN interferon, IM intramuscular, TER teriflunomide
`
`Page 6 of 14
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`atthe NLM and maybe
`Subject US Copyright Laws
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`
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`

`

`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
`
`the initial proportions of patients
`national survey study,
`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 lingolimod,
`teri-
`flunomide, dimethyl
`fumarate.
`and natalizumab,
`the
`hazard ratios of disease progression for DMDs compared
`with placebo reported in phase II] placebo-controlled
`trials were used to derive the 1—month transition proba—
`bilities for each DMD. For the IFN-Ilh, arm,
`the hazard
`ratio from the head-to-head trial TRANSFORMS between
`
`fingolimod and IFN-{ila was also used to estimate tran-
`sition probabilities {3].
`The transition probabilities of relapses for patients in
`SM were obtained from the placebo group in the F'I‘Y720
`Research Evaluating Effects of Daily Oral Therapy in
`Multiple Sclerosis (FREEDOMS) trial [33]. Hazard ratios
`of
`relapses between DMDs
`(terifiunomide, dimethyl
`fumarate, and natalizumab) and placebo were used to
`derive the transition probabilities to relapse state for the
`DMDs. For patients treated with fingolimod and lFN-Blm
`relapse probabilities were estimated by using the data in the
`TRANSFORMS trial
`[3]. All discontinuation rates were
`
`extracted from the corresponding phase III clinical trials.
`After discontinuation of the first-line therapy, the assign-
`ment ratio between natalizurnab and SM was assumed to be
`equal
`in the base case scenario, and extreme cases were
`tested in sensitivity analyses. Since the mortality rate due
`to MS is 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 RC'l‘s, 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 [FN'Bui were obtained from the Presser et al.
`[40] quality—of—lil'e 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 Presser et a].
`[41] study was used because
`standard-gamble was thought to be the gold standard in
`preference elicitation since it is the only method that esti—
`mates Von-Neumann—Morgenstern
`utility
`(preference
`measured under uncertainty) [4|]. Also, since this study
`was performed from a societal perspective, use of com-
`munity preferences was more appropriate as it reflected the
`society’s preference on the resource allocation 142]. Dis-
`utility for relapses was based on the Kobelt et a1. study
`[19]. For the effects of fingolimod and natalizumab, though
`there was evidence that fingolimod and natalizumab could
`improve the quality oflife of MS patients significantly [43‘
`45 i, no Study on utility impacts was available. Therefore, to
`be conservative,
`the disutility for fingolimod and natal-
`izumah was assumed to be 0 in the base case scenafio-
`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 teriilunomide, so the impact of teriflun-
`omide on utility was assumed to be 0 in the base case
`analysis [46]. Dimethyl furnarate has been reported to have
`significant improvements in physical and mental aspects of
`health and functioning, where the change in EQ-SD value
`was (1.01 [47, 48]. The base case utilities and the effects of
`DMDs on 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 of stratified EDSS score, which corresponded to each
`health state in our model. The costs included costs of
`
`tests, drugs
`inpatient care, ambulatory care,
`hospital
`(DMDs and 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
`
`L\ Adis
`
`3x2...
`
`Page 7 of 14
`
`This material wascepieo
`at the NLM and maybe
`Subject US Copyright Laws
`
`Page 7 of 14
`
`

`

`Cost Effectiveness 01' Oral Discase~Morlifying Drugs Versus 1M [FN-[iln 75
`
`
`
`Table 2 Parameters and range
`.
`.
`.
`.
`.
`m one-way sensitivny analysis
`
`[71
`17]
`[7]
`
`-
`Onekw-t SA rm 0"
`Base cast:
`.-
`‘
`1’1r'm'
`___—___—__,__.__.—.—_.._..————_——_—_
`1‘1 um.
`‘
`.y
`‘ 9
`Summit
`Monthly probability of disease progression (SM)
`0035 0.0—2.5
`EDSS 3.0—5.5
`EDSS 0.0—7.5
`
`NM
`
`0.005700
`0.007194
`0.005700
`
`Monthly probability of progressing to death
`EDSS 0.0—2.5
`EDSS 3.0—5.5
`EDSS 00.7.5
`EDSS 8.0—9.5
`
`0.001684
`0.002343
`0.003121
`0.004457
`
`Annual relapse rate for SM
`Annual relapse rate for FIN
`Annual relapse rate for [M lFN-fim
`HR of disease progression
`FIN vs. SM
`
`1M MIN-Ill.I vs. FlN
`TER vs. SM
`DP vs. SM
`NAT vs. SM
`HR of annual relapse rate
`'I‘ER vs. SM
`DP vs. SM
`NAT vs. SM
`Annual discontinuatiOn nth: for FIN
`Annual discontinuation rate for 1M lFN—B...
`
`Discontinuation rate for TER. 2 year
`Discontinuation rate for DF, 2 year
`Discontinuation rate for NAT, 2 year
`Assignment ratio between NAT and SM
`Utilities estimates
`
`Utility EDSS 11.0—04.5
`Utility EDSS 10—0—55
`Utility EDSS 00—0—15
`Utility EDSS B.0—0—‘).5
`Disutility for relapse
`Disutility for [M IFN-[tm
`impact 01' FIN on utility
`impact 01' TER on utility
`Impact of BF on utility
`Impact of NAT on utility
`Monthly costs, 2012 US dollars
`WAC for FIN
`WAC for 1M IFN-B...
`WAC for NAT
`WAC for TER
`WAC for DF
`
`-
`
`DF dimethyl fumztrate. EDSS
`Expanded Disability Status 8001:.
`
`NAT ttatttlizuntttb, SA sensitivity
`“"“iY-‘ii-‘h 3M SYII‘IPIUII‘
`tttanagcmcnt. TER tcrifiuttomidc,
`WAC wholesale average cost
`.. 3:25 % unless indicated
`
`cost of EDSS 0.0—2.5
`Cost of 1.31335 33.55
`Comm
`
`C0“ 9f EDSS 8-9’9-5
`Cost of relapse
`Discount rate
`
`'l'imc horizon
`
`Page 8 of 14
`
`This material was cop-tad
`a: the NLM and maybe
`Subject L15 Copyright Laws
`
`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
`0.0113
`0.5:0.5
`
`0.899
`0.821
`0.769
`0.491
`--U.09'-l
`—0.1 15
`0
`D
`0.01
`0
`
`$4.164
`$1535
`$3,320
`$3.704
`$3,346
`
`3615
`$1.289
`
`$6.369
`$5.008
`003
`
`5 years
`
`NIA
`
`NIA
`0.120
`0.248
`
`0.525
`
`1.015
`0.525
`0.465
`N/A
`
`0.540
`0.383
`MA
`0.077
`0,089
`
`0.199
`0.233
`NA
`0:1
`
`0.674
`0.016
`0.577
`0.368
`—0.0'1'l
`#0036
`-0.03
`—0.03
`—0.03
`NM
`
`$3.123
`$2376
`$2.490
`$2.778
`$2,509
`
`$1.298
`$2.768
`$4.04
`
`$85393
`$3,756
`0
`
`2 years
`
`0.200
`0.413
`
`0.875
`
`1.692
`0.1175
`0.775
`
`0.900
`0.038
`
`0.128
`0.148
`
`0.332
`0.388
`
`1:0
`
`1
`1
`0.961
`0.614
`—0.1 18
`—0.144
`0.03
`0.03
`0.03
`
`$5,204
`$4.794
`$4,150
`$4,630
`$4,182
`
`$2.163
`$4.614
`.6...
`
`513-439
`$6,259
`0-05
`
`10 years
`
`[39]
`I391
`[39]
`'391
`
`[jg]
`[3]
`l3]
`
`[33}
`
`[3;
`[4]
`15]
`[34]
`
`[4]
`[5]
`[34]
`[3]
`[3}
`
`[4}
`15]
`[34]
`
`(40'
`[40]
`[40}
`[40]
`119}
`{an}
`[43, 44]
`[46]
`[47‘ 431
`145]
`
`1501
`1501
`[50]
`[59]
`150]
`
`[19]
`[19]
`.9.
`
`[19]
`[5]]
`
`A Adis
`
`Page 8 of 14
`
`

`

`X. Zhang er 3],
`76
`_________________.___.—-———-—-~————-————
`
`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 of life for patients with RRMS in the USA
`[5 l].
`
`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 lFN-B,u and the robustness of the optimal
`therapy selection by using INMB as the 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
`
`parameter variation resulted in a major change in conclu-
`sion [49]. Tornado diagrams were plotted in 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 ol’ the base case results was also tested
`
`by probabilistic sensitivity analysis based on a second
`order Monte Carlo simulation (LOGO 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
`
`[53L Health care costs for each health state and
`and l
`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.
`
`Table 3 Results for the base case scenario (WTP = 1333150000)
`lNMB vs. lM lFN-Blu
`DMDS
`Cost
`QALY
`NMB
`lCER: FIN vs. TER
`ICER vs. lM “TN-[5h|
`_______________—._.—.___——____—_______
`
`[M lFN-Biu
`TER
`FIN
`DP"
`
`$223,606
`$226,085
`$239,947
`$200, I45
`
`3.34
`3.68
`3.69
`3.72
`
`$276,745
`$326,525
`$3 l 3,3 [2
`$357,356
`
`.—
`$49,780
`$36,567
`3580,61 l
`
`$7,! l5
`
`$46,328
`Dominant
`
`—
`
`$3.20!,672
`_
`
`D!" dimethyl l‘umarate, DMD: disease—modifying drugs, MN tmgolnuod, ICU? incremental cost-effectiveness ratio, IFN interferon, [M intra—
`muscular, INMB incremental net monetary benefit, NMII net monetary benefit, QALY quality-adjusted life year, TER terillttnomide, WTP
`willingness to pay
`
`Fig. 2 Net monetary benelits of
`the disease-modifying drugs.
`IFN interferon.
`1M intramuscular
`
`500000
`
`400000
`
`300000
`
`200000
`
`100000
`
`-100000
`
`-200000
`
`-300000
`
`
`
`Netmonetarybenefits
`
`
`
`
`100000
`
`120000
`140000
`160000
`180000
`
`
`
`
`80000
`
`
`
`
`
`Dimethvl fumarate
`
`Willingness~to~pay
`----- Teriflunomide
`
`--------- Fingolimod
`
`— ~ — IM tFN [3-1.]
`
`A Adis
`
`Page 9 of 14
`
`This matariai was cal-pied
`a: the NLM and may be
`in Inject US Copyright Laws
`
`Page 9 of 14
`
`

`

`77
`Cost Effectiveness of Oral Disease-Modifying Drugs Versus lM‘iFN—Bm
`
`Fig. 3 Results for one-way
`sensitivity analysis. DF
`dimelhyl futililt'tlie. EDSS
`Expanded Disability Status
`Scale, FIN fiiigotinmtt, 11W
`inter