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Cost-utility of First-line Disease-modifying Treatments for Relapsing–Remitting Multiple Sclerosis

Open AccessPublished:February 13, 2017DOI:https://doi.org/10.1016/j.clinthera.2017.01.028

      Abstract

      Purpose

      This study evaluated the cost-effectiveness of first-line treatments of relapsing–remitting multiple sclerosis (RRMS) (dimethyl fumarate [DMF] 240 mg PO BID, teriflunomide 14 mg once daily, glatiramer acetate 20 mg SC once daily, interferon [IFN]-β1a 44 µg TIW, IFN-β1b 250 µg EOD, and IFN-β1a 30 µg IM QW) and best supportive care (BSC) in the health care payer setting in Finland.

      Methods

      The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained, 3%/y discounting). Markov cohort modeling with a 15-year time horizon was employed. During each 1-year modeling cycle, patients either maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS) or showed EDSS progression in SPMS, experienced relapse with/without hospitalization, experienced an adverse event (AE), or died. Patients׳ characteristics, RRMS progression probabilities, and standardized mortality ratios were derived from a registry of patients with MS in Finland. A mixed-treatment comparison (MTC) informed the treatment effects. Finnish EuroQol Five-Dimensional Questionnaire, Three-Level Version quality-of-life and direct-cost estimates associated with EDSS scores, relapses, and AEs were applied. Four approaches were used to assess the outcomes: cost-effectiveness plane and efficiency frontiers (relative value of efficient treatments); cost-effectiveness acceptability frontier, which demonstrated optimal treatment to maximize net benefit; Bayesian treatment ranking (BTR); and an impact investment assessment (IIA; a cost-benefit assessment), which increased the clinical interpretation and appeal of modeled outcomes in terms of absolute benefit gained with fixed drug-related budget. Robustness of results was tested extensively with sensitivity analyses.

      Findings

      Based on the modeled results, teriflunomide was less costly, with greater QALYs, versus glatiramer acetate and the IFNs. Teriflunomide had the lowest ICER (24,081) versus BSC. DMF brought marginally more QALYs (0.089) than did teriflunomide, with greater costs over the 15 years. The ICER for DMF versus teriflunomide was 75,431. Teriflunomide had >50% cost-effectiveness probabilities with a willingness-to-pay threshold of <€77,416/QALY gained. According to BTR, teriflunomide was first-best among the disease-modifying therapies, with potential willingness-to-pay thresholds of up to €68,000/QALY gained. In the IIA, teriflunomide was associated with the longest incremental quality-adjusted survival and time without cane use. Generally, primary outcomes results were robust, based on the sensitivity analyses. The results were sensitive only to large changes in analysis perspective or mixed-treatment comparison.

      Implications

      The results were sensitive only to large changes in analysis perspective or MTC. Based on the analyses, teriflunomide was cost-effective versus BSC or DMF with the common threshold values, was dominant versus other first-line RRMS treatments, and provided the greatest impact on investment. Teriflunomide is potentially the most cost-effective option among first-line treatments of RRMS in Finland.

      Key words

      Introduction

      Multiple sclerosis (MS)—a chronic progressive, autoimmune, inflammatory disease—affects >2 million people worldwide. Approximately 89% of cases are classified as relapsing–remitting MS (RRMS) at the time of diagnosis.
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      Modeling the cost-effectiveness of a new treatment for MS (natalizumab) compared with current standard practice in Sweden.
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      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
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      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
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      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
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      MS treatment with disease-modifying therapies (DMTs) is aimed at decreasing the inflammatory activity leading to relapses, stopping or slowing progression of residual disability, and, eventually, delaying the progression to the secondary progressive phase. However, long-term prognosis among treated patients is largely unknown. Based on Finnish drug reimbursement and sales data,
      Kelasto
      Number of individuals with reimbursements and prescriptions.
      commonly used first-line DMTs include injectable DMTs, namely glatiramer acetate (GA), interferon (IFN)-β1a IM, IFN-β1a SC, and IFN-β1b SC.
      Dimethyl fumarate (DMF) and teriflunomide are new oral DMTs reimbursed as the first-line treatment of RRMS in Finland. The efficacy and safety of DMF 240 mg BID for established MS have been studied in the Phase III CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis)
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      trial (NCT00622700). Effectiveness of teriflunomide compared with IFN-β1b SC has been demonstrated in the Phase III TENERE (Teriflunomide and Rebif® in Patients with Relapsing Multiple Sclerosis)
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      trial (NCT00883337).
      We evaluated the cost-utility of injectable and oral first-line DMTs in the Finnish population of patients with RRMS, based on a decision-analytical model. To our knowledge, there are no previously published journal articles on the cost-utility of first-line oral DMTs in a European setting or on oral and injectable DMTs for first-line treatment of RRMS. In addition, progression of RRMS in Finnish patients has not been assessed before, and the 4 different approaches elaborating the key results from MS cost-utility analysis have not been previously reported.

      Materials and Methods

      The cost-utility of the first-line DMTs in the Finnish RRMS population was assessed in a decision-analytical modeling framework
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      by implementing a Markov cohort model with mutually exclusive health states in Excel 2007, including Visual Basic for Applications (Microsoft Corporation, Redmond, Washington). The modeling approach followed the Finnish guidance for health economic analyses.
      Pharmaceuticals Pricing Board
      Composing health economic evaluation for the pricing and reimbursement application.
      The primary outcome of analysis was the modeled incremental cost-effectiveness ratio (ICER), reported as Euros per quality-adjusted life-year (€/QALY) gained. The interpretation of ICER is challenging in Finland because the decision maker’s willingness-to-pay (WTP) threshold per QALY gained has not been publicly declared,
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      could be applicable in Finland, so that values of <~€25,000 or €25,000–37,000/QALY gained would indicate most plausible or plausible cost-effectiveness, respectively; and, on average, €55,000/QALY gained could be acceptable for end-of-life treatment based on the UK population-weighted decisions. This applicability of UK thresholds is based on the observation that many articles from Finland
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      The Finnish Medicines Agency has considered that €68,000/QALY gained approaches the maximum cost-effectiveness threshold for a life-threatening cancer
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      The health care payer setting, which is recommended in the Finnish guidance for health economic analyses,
      Pharmaceuticals Pricing Board
      Composing health economic evaluation for the pricing and reimbursement application.
      was used in the modeling. This model includes direct health and social care costs, and excludes income transfers (taxes) and indirect costs (eg, time costs, disability payments, presenteeism, absenteeism, and informal care). A scenario analysis, including productivity losses,
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      was performed to assess the robustness of this direct-costing perspective. A summary of the modeled key research questions is given in Table I as an extended PICO framework, which is used to capture and clarify the essential parts of complicated cost-effectiveness assessment in a sensible order (namely, PICOSTEPS: P, patients; I, interventions; C, comparator; O, outcomes; S, setting; T, time horizon; E, effects; P, perspective; and S, sensitivity analyses).
      Table IPICOSTEPS: Summary of the research questions.
      PICOSTEPSDescription
      P: PatientsFinnish adults with incident RRMS and EDSS scores 0.0–6.5 at baseline based on data from a Finnish MS registry
      I: InterventionsDMTs: DMF 240 mg PO BID, teriflunomide 14 mg once daily, GA 20 mg SC once daily, IFN-β1a 44 µg SC TIW, IFN-β1b 250 µg SC EOD, IFN-β1a 30 µg IM QW
      C: ComparatorCommon comparator: BSC (trial placebo)
      O: OutcomesPrimary: ICER given as the cost/QALY gained based on the direct cost
      Secondary: disaggregated and total QALYs (based on EQ-5D-3L) and costs, life-years, years without impaired mobility (EDSS <6; ie, years without cane use), cost-effectiveness plane and efficiency frontiers, cost-effectiveness acceptability frontiers, Bayesian treatment ranking, and cost–benefit assessment. Discounting: 3%/y
      S: SettingProbabilistic decision analytical modeling (Markov cohort model), including 21 health states reflecting the disease progression (modified by treatment efficacy); and events reflecting relapses, AEs, and withdrawals
      T: Time horizon15 years, based on the follow-up data from the Finnish registry, time since diagnosis in a Finnish cost and EQ-5D-3L MS study,
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      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
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      E: EffectsRRMS progression: Finnish MS registry data (see Supplemental Material A in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028). SPMS progression: London Ontario MS registry (see Supplemental Material A in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028). Relapse rates: published elsewhere.
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      Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis.
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      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
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      • et al.
      Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use.
      Mortality: Finnish MS registry data and statistics
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      with EDSS-related
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      Causes of death among patients with multiple sclerosis.
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      Relapse costs: Finnish MS registry data. Relapse disutility: Finnish study
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      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      accounting for hospitalization status and duration.
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      duration, costs, and occurrence (see Supplemental Material B in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028).
      P: PerspectiveFinnish payer perspective. A scenario analysis with a societal perspective.
      S: Sensitivity analyses25 deterministic scenarios: impact of modeling assumptions, result robustness, and generalizability
      Probabilistic sensitivity analysis: joint uncertainty of the input estimates
      AE = adverse event; BSC = best supportive care; DMF = dimethyl fumarate; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; EQ-5D-3L = EuroQol Five-Dimensional Questionnaire, Three-Level Version; GA = glatiramer acetate; ICER = incremental cost-effective ratio; IFN = interferon; MS = multiple sclerosis; QALY = quality-adjusted life-year; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis.
      A relatively straightforward, limited cost–benefit analysis (clinical value analysis) approach was recently developed.
      • Soini E.
      • Hautala A.
      • Poikonen E.
      • et al.
      Cost-effectiveness of first-line chronic lymphocytic leukemia treatments when full-dose fludarabine is unsuitable.
      As a secondary complementary analysis, an impact investment assessment (IIA) was carried out to increase the clinical appeal and interpretation of the primary outcome results.
      • Soini E.
      • Hautala A.
      • Poikonen E.
      • et al.
      Cost-effectiveness of first-line chronic lymphocytic leukemia treatments when full-dose fludarabine is unsuitable.
      The IIA here covered a fixed drug-related budget based on the most affordable DMT and incremental quality-adjusted survival or time to cane use (EDSS score, 6) versus best supportive care (BSC; trial comparator). The outcome (impact on investment [II]) of the IIA was the duration of benefit obtained in comparison with BSC with the fixed budget. This IIA incorporated an explicit minimal willingness-to-invest (WTI) value for DMT based on the most affordable DMT and, thus, demonstrated the mean absolute cost–benefit in terms of a single unit:
      II=(DrughealthbenefitivsBSC)(AssumeddrugrelatedminimalWTI)(Drugrelatedcosti)
      (Equation 1)


      where i indicates a particular drug treatment.
      Consequently, the result of the IIA is a standardized benefit (II) obtained with the given WTI (in fact, the WTI can be greater than the minimum assumed here, and the benefit increases accordingly).

      Patients

      Finland’s MS research registry data were used to define the cohort characteristics in the model. Based on the MS research registry data (713 ambulatory patients from Finland, with MS diagnosed in 1991–2010 and an EDSS score of 0–6.5 observed at baseline; see Supplemental Material A in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028), the mean age of modeled patients was 35.64 years, and the female/male ratio was 2.57. The distribution of EDSS scores at baseline is shown in Figure 1.
      Figure 1.
      Figure 1Expanded Disability Status Scale (EDSS) score distribution at the initiation of modeling.

      Model

      The clinical course of MS was modeled (Figure 2)
      • Chilcott J.
      • McCabe C.
      • Tappenden P.
      • et al.
      Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis.
      • Gani R.
      • Giovannoni G.
      • Bates D.
      • et al.
      Cost-effectiveness analyses of natalizumab (Tysabri) compared with other disease-modifying therapies for people with highly active relapsing-remitting multiple sclerosis in the UK.
      to capture all relevant evidence,
      • Briggs A.
      • Claxton C.
      • Sculpher M.
      Decision modelling for health economic evaluation.
      Pharmaceuticals Pricing Board
      Composing health economic evaluation for the pricing and reimbursement application.
      National Institute for Health and Care Excellence (NICE)
      Guide to the Methods of Technology Appraisal 2013.
      as no direct comparison is currently available. Models are always hypothetical and contain an element of uncertainty, but when relying on conservative and fair structure and estimates—and keeping the modeling assumptions in mind—they can produce useful information for decision making.
      Figure 2.
      Figure 2Simplified presentation of the Markov model and its key health states. Relapses and adverse events are not depicted. EDSS = Expanded Disability Status Scale; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary-progressive multiple sclerosis.
      In the model shown in Figure 2, patients with RRMS either maintained the same EDSS or transited to another EDSS health state as the disease progressed, developed secondary progressive MS (SPMS), transited to another EDSS state in SPMS, or died (EDSS score, 10; absorbing state) within the 1-year model cycles. Within each cycle, patients experienced a relapse (with/without hospitalization) and/or an adverse event (AE). The relative effects of DMTs were implemented as modifiers of the modeled clinical course of MS. Midcycle estimates (life-table method of half-cycle correction
      National Institute for Health and Care Excellence (NICE)
      Dimethyl fumarate for treating relapsing-remitting multiple sclerosis. NICE technology appraisal guidance 320.
      • Barendregt J.J.
      The life table method of half cycle correction: getting it right.
      • Naimark D.M.
      • Kabboul N.N.
      • Krahn M.D.
      The half-cycle correction revisited: redemption of a kludge.
      ) were used to avoid over- or underestimation of modeled outcomes.

      Disease Progression

      Disease progression and relapses were modeled independently. Disease progression in terms of the EDSS score development during RRMS was estimated from Finland’s MS research registry data, consisting of 2299 EDSS measurements. The probability of transiting from RRMS to SPMS was estimated, and EDSS development during SPMS was based on results from the London Ontario registry of MS (see Supplemental Material A in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028). For the origins of registry, see Weinshenker et al.
      • Weinshenker B.G.
      • Bass B.
      • Rice G.P.
      • et al.
      The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.
      The relapse rates in patients not receiving DMTs were taken from published references.
      Biogen Idec
      • Patzold U.
      • Pocklington P.R.
      Course of multiple sclerosis: first results of a prospective study carried out of 102 MS patients from 1976-1980.
      The percentage of relapses leading to hospitalization (30.7%) was estimated from the TEMSO trial.
      • Miller A.E.
      • O’Connor P.
      • Wolinsky J.S.
      • et al.
      Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis.
      • O’Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      • O’Connor P.W.
      • Lublin F.D.
      • Wolinsky J.S.
      • et al.
      Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use.
      The annual probability of death was modeled based on Finland’s general population mortality rates by applying the observed MS female/male ratio of 2.57 from Finland’s MS research registry data to Finland’s all-cause age- and sex-specific mortality rates from the year 2014,
      Statistics Finland
      Deaths: Statistics Finland [in Finnish].
      multiplying the sex-weighted general population mortality rate by the EDSS-specific standardized mortality ratio, and converting the result to give the probability.
      • Fleurence R.L.
      • Hollenbeak C.S.
      Rates and probabilities in economic modelling: transformation, translation and appropriate application.
      The EDSS-specific standardized mortality ratio was estimated from Finland’s MS research registry results
      • Sumelahti M.L.
      • Hakama M.
      • Elovaara I.
      • Pukkala E.
      Causes of death among patients with multiple sclerosis.
      by using linear interpolation:
      Standardizedmortalityratio=0.515EDSS+1.000
      (Equation 2)


      Treatment Efficacy and Tolerability

      Treatment efficacy was assessed by common MS study outcomes: sustaining the same disability status for 12 weeks, annualized relapse rate (ARR), and relapses. Persistence was assessed by withdrawal rates, and tolerability, by AEs. Relative rates of hospitalization in the model were derived from the following clinical trials: IFN-β1a SC, CARE MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis)
      • Cohen J.A.
      • Coles A.J.
      • Arnold D.L.
      • et al.
      Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
      (assumed to apply to GA and IFN-β1b SC); IFN-β1a IM, TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis)
      • Haas J.
      • Hartung H.P.
      • von Rosenstiel P.
      • et al.
      Fingolimod reduces the number of severe relapses in patients with relapsing multiple sclerosis: results from phase III TRANSFORMS and FREEDOMS studies.
      ; and teriflunomide, TEMSO
      • O’Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      (assumed to apply to DMF). Withdrawals were assumed to happen at the initiation of a new model cycle (but not at the start of the first cycle), and patients were assumed to discontinue their current treatment when they progressed from RRMS to SPMS.
      Disability progression, ARR, and withdrawal rates were modeled based on a mixed-treatment comparison assessed by the National Institute for Health and Care Excellence.
      • Cutter G.
      • Fahrbach K.
      • Huelin R.
      • et al.
      Relative efficacy of teriflunomide 14 mg in relapsing MS: a mixed-treatment comparison.
      National Institute for Health and Care Excellence (NICE)
      Final Appraisal Determination—Teriflunomide for Treating Relapsing-Remitting Multiple Sclerosis.
      To account for new MS diagnostics, earlier treatment, and evidence of decreased ARR over time, the base case analysis included trials that enrolled ≥80% of patients who had RRMS and had been recruiting patients since 2000. In addition, multiway sensitivity analyses (disability progression, ARR, withdrawal rates) of mixed-treatment comparison without year limit and with or without adjustment for placebo relapses were performed.
      Treatment safety was modeled using reported AEs from clinical trials or earlier health technology assessments, their costs, and QoL effects (see Supplemental Material B in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028). AEs reported with similar terms were assumed to be treated similarly and to result in similar QoL loss.

      Quality-adjusted Survival

      The EuroQol Five-Dimensional Questionnaire, Three-Level Version (EQ-5D-3L) QoL for EDSS scores was modeled on the basis of data from DEFENSE (Burden of Illness in Multiple Sclerosis),
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      a recent cross-sectional survey from Finland. The occurrence and impact
      • Soini E.
      • Hallinen T.
      Cost-utility of agomelatine, venlafaxine and placebo in the treatment of major depressive disorder (MDD) in Finland—economic modelling study using representative population data.
      of AEs (see Supplemental Material B in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028) and relapses
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      • Prosser L.A.
      • Kuntz K.M.
      • Bar-Or A.
      • Weinstein M.C.
      Cost-effectiveness of interferon beta-1a, interferon beta-1b, and glatiramer acetate in newly diagnosed non-primary progressive multiple sclerosis.
      were accounted for. Finland’s EDSS-related QoL values
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      were deemed acceptable because the mean EQ-5D-3L score in EDSS 0-1 was in line with values from the general population of Finland.
      • Saarni S.I.
      • Harkanen T.
      • Sintonen H.
      • et al.
      The impact of 29 chronic conditions on health-related quality of life: a general population survey in Finland using 15D and EQ-5D.
      However, the study from Finland
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      did not specify QoL related to relapse with and without hospitalizations.
      Findings from studies suggest greater disutility for relapse with hospitalization compared with relapses without hospitalization.
      • Orme M.
      • Kerrigan J.
      • Tyas D.
      • et al.
      The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK.
      • Prosser L.A.
      • Kuntz K.M.
      • Bar-Or A.
      • Weinstein M.C.
      Cost-effectiveness of interferon beta-1a, interferon beta-1b, and glatiramer acetate in newly diagnosed non-primary progressive multiple sclerosis.
      In a US study, the QoL losses in relapsed patients with and without hospitalization were reported as –0.302 and –0.091, respectively.
      • Prosser L.A.
      • Kuntz K.M.
      • Bar-Or A.
      • Weinstein M.C.
      Cost-effectiveness of interferon beta-1a, interferon beta-1b, and glatiramer acetate in newly diagnosed non-primary progressive multiple sclerosis.
      The latter estimate is similar to the Finnish relapse loss, that is, –0.064,
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      which used an extensive 1-year recall period and did not make a distinction between hospitalized and nonhospitalized patients or number of relapses.
      To approximate the QoL loss associated with hospitalizations, the Finnish QoL loss was weighted with the observed ratio between the QoL losses for hospitalized and nonhospitalized relapses in the US study
      • Prosser L.A.
      • Kuntz K.M.
      • Bar-Or A.
      • Weinstein M.C.
      Cost-effectiveness of interferon beta-1a, interferon beta-1b, and glatiramer acetate in newly diagnosed non-primary progressive multiple sclerosis.
      (ratio –0.302/–0.091 = 3.3187) to obtain disutility for hospitalized patients in Finland. The applied QoL losses in relapsed patients with and without hospitalization in the model were –0.212 and –0.064, respectively. The QoL effect of relapse was assumed to last for 3 months.
      • Orme M.
      • Kerrigan J.
      • Tyas D.
      • et al.
      The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK.

      Costs

      Annual DMT cost was calculated using the indicated mean dose of each drug and number of doses per year (365.25 d/y), determined for each treatment regimen based on the product labeling. For drugs with multiple package sizes, the drug costs were estimated by weighting of the package costs by their estimated market share (Table II). A 100% dose intensity and adherence were assumed.
      Table IIDrug-related use and costs.
      DMTDose/Amount per PackageCost per Package,€
      Drug costs are at January 2016 values.
      Dosage (SPCs)Use, %Cost, €
      DMF 120 mg
      Trademark: Tecfidera® (Biogen, Weston, Massachusetts).
      120 mg, 14 tablets188.37120 mg PO BID1.9214,435/1st y
      DMF 240 mg
      Trademark: Tecfidera® (Biogen, Weston, Massachusetts).
      240 mg, 56 tablets1151.56240 mg PO BID15.33
      240 mg, 168 tablets3319.3382.75
      DMF 240 mg
      Trademark: Tecfidera® (Biogen, Weston, Massachusetts).
      240 mg, 56 tablets1151.56240 mg PO BID15.3314,523/2nd y
      240 mg, 168 tablets3319.3384.67
      GA 20 mg
      Trademark: Copaxone® (Teva, Ulm, Germany).
      20 mg/mL, 28 × 1 mL836.1120 mg SC once daily100.0010,907
      IFN-β1a 30 µg IM
      Trademark: Avonex® (Biogen).
      30 µg/0.5 mL, 4 × 0.5 mL814.9030 µg SC QW100.0010,630
      IFN-β1a 44 µg SC
      Trademark: Rebif® (EMD Serono, Rockland, Massachusetts).
      44 µg/0.5 mL, 12 × 0.5 mL897.8344 µg SC TIW100.0011,712
      IFN-β1b 250 µg SC
      Trademark: Betaferon® (Bayer Pharmaceuticals, West Haven, Connecticut).
      250 µg/mL, 15 × 1 mL793.08250 µg SC EOD100.009656
      Teriflunomide 14 mg
      Trademark: Aubagio® (Genzyme [a Sanofi Company], Cambridge, Massachusetts).
      14 mg, 28 tablets1017.8914 mg PO once daily15.3312,023
      14 mg, 84 tablets2712.7984.67
      DMT = disease-modifying therapy; DMF = dimethyl fumarate; GA = glatiramer acetate; IFN = interferon; SPC = summary of product characteristics.
      low asterisk Drug costs are at January 2016 values.
      Trademark: Tecfidera® (Biogen, Weston, Massachusetts).
      Trademark: Copaxone® (Teva, Ulm, Germany).
      § Trademark: Avonex® (Biogen).
      Trademark: Rebif® (EMD Serono, Rockland, Massachusetts).
      Trademark: Betaferon® (Bayer Pharmaceuticals, West Haven, Connecticut).
      # Trademark: Aubagio® (Genzyme [a Sanofi Company], Cambridge, Massachusetts).
      Administration, monitoring (Table III), and AE costs (see Supplemental Material B in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028) were calculated on the basis of resource consumption multiplied by the associated unit costs. DMT-associated resources were based on the product labeling, recommendations in Finland,
      Finnish Medical Society Duodecim, Finnish Neurological Society Working Group
      MS Disease.
      • Elovaara I.
      • Soilu-Hanninen M.
      • Kuusisto H.
      • et al.
      Magnetic resonance imaging of the brain in the monitoring of immune therapy of multiple sclerosis.
      • Remes A.
      • Airas L.
      • Atula S.
      • et al.
      Update on current care guideline: multiple sclerosis.
      publications or earlier assessments (see Supplemental Material B in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028), and clinical practice.
      Table IIIMonitoring and disability (EDSS)-related resource use and costs.
      MonitoringUnit Cost, €
      Pre-2013 nontariff costs14,68,69 were indexed to the 2014 price level using official communal price index for health care services.71
      Resources, First Year/Later Year
      Unless otherwise noted.
      DMFGAIFNsTeriflunomideBSC
      Specialist visit340.76, Including 5% copayment
      • Kapiainen S.
      • Väisänen A.
      • Haula T.
      Health and Social Care Costs in Year 2011 in Finland.
      2/12/12/12/10/0
      SC training50.97 Nurse visit
      • Kapiainen S.
      • Väisänen A.
      • Haula T.
      Health and Social Care Costs in Year 2011 in Finland.
      0/01/01/00/00/0
      Laboratory fee
      Fixed laboratory fee for each test taking time.
      5.47
      • Hujanen T.
      • Kapiainen S.
      • Tuominen U.
      • Pekurinen M.
      Health care unit costs in year 2006 in Finland.
      4/40/04/117/60/0
      ALT1.00
      FimLab
      Pricelist for Laboratory Tests.
      4/10/04/117/60/0
      GGT, creatinine2.00
      FimLab
      Pricelist for Laboratory Tests.
      4/10/00/00/00/0
      BC1.55
      FimLab
      Pricelist for Laboratory Tests.
      0/00/04/10/00/0
      FBC6.60
      FimLab
      Pricelist for Laboratory Tests.
      4/40/00/04/10/0
      MxA92.50
      • Hospital Tampere University
      Services and Prices, 2013.
      0/00/01/10/00/0
      TSH2.50
      FimLab
      Pricelist for Laboratory Tests.
      0/00/01/00/00/0
      UT5.84
      • Hujanen T.
      • Kapiainen S.
      • Tuominen U.
      • Pekurinen M.
      Health care unit costs in year 2006 in Finland.
      4/10/00/00/00/0
      MRI, head335.58
      • Kapiainen S.
      • Väisänen A.
      • Haula T.
      Health and Social Care Costs in Year 2011 in Finland.
      1/0.51/0.51/0.51/0.50/0
      Phone call
      Phone call after laboratory tests if specialist visit not arranged.
      9.56 After tests
      • Kapiainen S.
      • Väisänen A.
      • Haula T.
      Health and Social Care Costs in Year 2011 in Finland.
      2/30/02/015/50/0
      Disability related
       EDSS score
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      0/12/34/56/78–9
       Direct health care costs, €
      Estimated costs of disease-modifying therapies (DMTs) were excluded based on the digitalization and estimation of DMT costs in Figure 4 in Ruutiainen et al.14
      1108/14462890/34703909/56567919/12,18515,718
       Direct non–health care costs, €49/8341693/45265767/15,28918,749/32,36468,852
      ALT = alanine aminotransferase; BC = blood count; BSC = best supportive care; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FBC = full blood count; GA = glatiramer acetate; GGT = gamma-glutamyl transferase; MRI = magnetic resonance imaging; MxA = protein induced by interferon-alfa/β; TSH = thyroid-stimulating hormone; UT = urine test.
      low asterisk Pre-2013 nontariff costs
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      • Hujanen T.
      • Kapiainen S.
      • Tuominen U.
      • Pekurinen M.
      Health care unit costs in year 2006 in Finland.
      • Kapiainen S.
      • Väisänen A.
      • Haula T.
      Health and Social Care Costs in Year 2011 in Finland.
      were indexed to the 2014 price level using official communal price index for health care services.
      Statistics Finland
      Price Index for Public Expenditures.
      Unless otherwise noted.
      Fixed laboratory fee for each test taking time.
      § Phone call after laboratory tests if specialist visit not arranged.
      Estimated costs of disease-modifying therapies (DMTs) were excluded based on the digitalization and estimation of DMT costs in Figure 4 in Ruutiainen et al.
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      In addition to the EQ-5D-3L QoL scores, which are hard to predict with common regressions,
      • Soini E.
      • Koskela T.
      • Ryynänen O.P.
      International normalized ratio (INR) monitoring and percent time in therapeutic INR range (TTR) have impact on patient’s quality of life? Application of beta regressions in a prospective 3 months setting.
      • Soini E.
      • Mäkirinne-Kallio N.
      • Martikainen J.
      • et al.
      Estimation of quality-adjusted survival with mild obstructive sleep apnoea and six quality of life (QoL) assessments: comparison between trapezoid rule, cross-sectional and mixed model estimates.
      the DEFENSE survey
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      assessed the costs of patients with MS in Finland. The EDSS-related direct costs were estimated based on data from the DEFENSE survey
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      and are reported in Table III. Because of limitations in the assessment of DEFENSE-derived relapse costs, the costs of relapses were estimated from other patients with RRMS in Finland (Tampere; N = 581; data included procedures, hospital visits, hospital stays, and unit cost
      • Hospital Tampere University
      Services and Prices, 2013.
      ) using semilog multivariate methodology explained elsewhere.
      • Soini E.
      • Leussu M.
      • Hallinen T.
      Administration costs of intravenous biologic drugs for rheumatoid arthritis.
      • Hallinen T.
      • Martikainen J.A.
      • Soini E.J.
      • et al.
      Direct costs of warfarin treatment among patients with atrial fibrillation in a Finnish health care setting.
      Based on this analysis, the additional costs per relapse with and without hospitalization were €5537.57 and €1297.41, respectively.
      In a scenario analysis, the relationship between EDSS and annual direct care costs (excluding DMT costs) was estimated based on a nonlinear interpolation of findings reported in a study from Finland,
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      as follows:
      Annualdirect(DMTsexcl.)costs=(128.44EDSS2+4266.60EDSS2480.10),
      (Equation 3)


      converted to 2014 real value
      Statistics Finland
      Price Index for Public Expenditures.
      and with EDSS 0 set to €0. The costs applied in this sensitivity analysis were well in line with those from other MS cost studies from Finland
      • Sillanpaa M.
      • Andlin-Sobocki P.
      • Lonnqvist J.
      Costs of brain disorders in Finland.
      and elsewhere.
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • et al.
      Modeling the cost-effectiveness of a new treatment for MS (natalizumab) compared with current standard practice in Sweden.
      Apart from the drugs, which were valued at January 2016 prices,
      Pharmaceuticals Pricing Board
      Reimbursable of Authorized Medicinal Products [in Finnish].
      health care costs were valued at 2013–2014 real prices. The required inflation adjustments were performed using Finland’s official price index for communal health care expenditures or income index.
      Statistics Finland
      Price Index for Public Expenditures.

      Statistics Finland. Income index. Helsinki: Statistics Finland; 2016.

      The modeled costs and health outcomes were discounted at 3%/y.

      Sensitivity and Generalizability of Results

      The robustness and generalizability of the base case results were assessed using various deterministic and probabilistic sensitivity analyses (DSA and PSA, respectively). The base case was based on most credible inputs. DSAs were based on 25 different scenarios, including major or noncredible changes in methods, health risks, treatment, costs, QoL, population, and settings. Means based on all 25 DSA scenarios were also calculated. The details of the DSAs are shown in Table IV.
      Table IVDetails of deterministic sensitivity analyses.
      CategoryScenario
      DiscountingNo discounting
      Discounting with 5%/y
      Health risksBritish Columbia, Canada, RRMS EDSS development, based on patients more than 28 years old
      • Palace J.
      • Bregenzer T.
      • Tremlett H.
      • et al.
      UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model.
      Alternative natural relapse source
      • Held U.
      • Heigenhauser L.
      • Shang C.
      • et al.
      Predictors of relapse rate in MS clinical trials.
      Rate for relapses leading to hospitalization based on the 1:2.75 ratio from Tampere data (26.7% of annual relapses result in hospitalization when adjusting for covariates including also EDSS score; N = 581; mean age at relapse, 40 y)
      Relapse time, 2 mo
      Relapse time, 4 mo
      TreatmentDMT discontinuation when EDSS 7 and over was reached, based on reimbursement criteria
      Disability progression and ARR set to the lower 95% credibility interval threshold of MTC results
      Disability progression and ARR set to the higher 95% credibility interval threshold of MTC results
      Alternative source disability progression, ARR, and withdrawal rates from the MTC: no year limit and adjustment for placebo relapses
      Alternative source disability progression, ARR, and withdrawal rates from the MTC: no year limit
      Time with AEs doubled (same as doubling AE disutility for those AEs that last a shorter time than the model cycle)
      Time with AEs halved (same as halving AE disutility)
      CostsEDSS costs based on the other Finnish source
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      at 2014 values
      Statistics Finland
      Deaths: Statistics Finland [in Finnish].
      Monitoring costs doubled
      Monitoring costs halved
      Relapse cost doubled
      Relapse cost halved
      AE costs doubled
      AE costs halved
      Societal approach (productivity loss included)
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.

      Statistics Finland. Income index. Helsinki: Statistics Finland; 2016.

      QoLAlternative EDSS QoL source
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      Similar QoL loss assumed for all relapses
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      Result generalizabilityTEMSO
      • Miller A.E.
      • O’Connor P.
      • Wolinsky J.S.
      • et al.
      Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis.
      • O’Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      • O’Connor P.W.
      • Lublin F.D.
      • Wolinsky J.S.
      • et al.
      Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use.
      patient characteristics and placebo transition probabilities for RRMS EDSS
      AE = adverse event; ARR = annualized relapse rate; EDSS = Expanded Disability Status Scale; MTC = mixed-treatment comparison; QoL = quality of life; RRMS = relapsing–remitting multiple sclerosis; TEMSO = Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis) Oral Teriflunomide for Patients with Relapsing Multiple.

      Probabilistic Sensitivity Analysis

      For PSA, a second-order Monte Carlo simulation was used to take into account the joint variation in the economic and clinical outcomes due to sampling uncertainty related to model parameters. The following distributions were used: β for ARR and withdrawal rates, γ for EDSS-related and treatment costs, log-normal for EDSS transitions, disease progression hazard rates, treatment effect on ARR, treatment effect on hospitalization relapse percentage and QoL, and Dirichlet distribution for the percentage of relapses involving hospitalization (see Supplemental Material C in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028). Based on the PSA, cost-effectiveness acceptability frontiers demonstrated optimal treatment to maximize net benefit with different WTP thresholds, and Bayesian treatment ranking ranked the best treatments.

      Results

      The average modeled base case results are reported in Table V. The mean projected 15-year total payer’s direct costs differed considerably (by 17.2%) between the most affordable (teriflunomide) and the most costly (IFN-β1b SC) DMT. The respective relative QALY gain difference was 9.3%. The maximum relative QALY difference was 10.6% between the 2 DMTs (DMF and IFN-β1b SC).
      Table VBase case results (3%/y discounting).
      OutcomeDMFTeriflunomideIFN-β1a SCGAIFN-β1a IMBSCIFN-β1b SC
      Primary
       ICER vs BSC, €/QALY gained33,68124,08157,690248,652244,105Dom.
       ICER vs teriflunomide, €/QALY gained75,431Dom.Dom.Dom.24,081Dom.
      Secondary
       ICER vs BSC, €/y without cane gained24,69217,37143,881236,722174,995Dom.
       ICER vs teriflunomide, €/y without cane gained59,512Dom.Dom.Dom.17,371Dom.
       Total costs/patient, €344,480337,749343,619364,279358,808328,403403,765
        Total disease costs280,427289,275301,543313,535314,881328,403356,527
         Direct disability67,63069,04771,43073,85173,57775,72181,726
         Relapses14,17015,43214,85413,67316,51918,29013,098
         Other direct198,626204,796215,258226,011224,784234,392261,703
        Total treatment costs64,05348,47442,07750,74443,927047,237
         Acquisition, administration60,93245,54839,01546,91640,741043,023
         Monitoring2976290625182653283303226
         AEs1452154411753530989
       Total QALYs/patient7.8087.7197.5957.4757.4567.3317.063
        Total disease QALYs7.8117.7207.5967.4767.4647.3317.064
         Disability QALYs7.9627.8847.7557.6247.6387.5247.206
         QALY loss due to relapses−0.151−0.164−0.159−0.147−0.175−0.193−0.142
         QALY loss due to AEs−0.003−0.001−0.001−0.001−0.0080.000−0.001
        Total life-years12.09812.09612.09212.08712.08812.08412.074
       Years without cane (EDSS <6)8.3938.2808.0897.8947.9167.7427.252
      AEs, adverse events; BSC = best supportive care; DMF = dimethyl fumarate; Dom. = dominated; GA = glatiramer acetate; ICER = incremental cost-effectiveness ratio; ICUR = incremental cost-utility ratio; IFN = interferon; QALY = quality-adjusted life-year.
      The modeled key outcome (ICERs €/QALY gained in comparison with BSC alone) ranged considerably, from 24,081 (teriflunomide) to 248,652 (GA) per QALY gained, and BSC dominated IFN-β1b SC in the base case. Teriflunomide was estimated to be less costly and more effective (dominant) than injectable first-line DMTs, and DMF had a high ICER of 75,431 versus teriflunomide, resulting from the marginally more QALYs (0.089) with DMF and higher costs versus teriflunomide over 15 years. (Table V and Figure 3).
      Figure 3.
      Figure 3Cost-effectiveness plane and cost-effectiveness efficiency frontiers. BSC = best supportive care; DMF = dimethyl fumarate; GA = glatiramer acetate; ICER = incremental cost-effectiveness ratio; IFN = interferon; QALY = quality-adjusted life-year.
      If the WTP threshold for additional QALY gained is set to the most plausible level (€25,000), only teriflunomide represents a cost-effective alternative to BSC alone, based on the modeling. If the WTP is between €37,000 (plausible) and €55,000 (end of life) per QALY gained, only teriflunomide and DMF represent cost-effective alternatives to BSC alone. However, with a modeled ICER of 75,414 for DMF versus teriflunomide, DMF is unlikely to be considered cost-effective in the Finnish setting given the unofficial assumed WTP thresholds detailed in Materials and Methods.
      The cost–benefit analysis type IIA utilized the minimal mean expected DMT-related discounted budget per patient (minimum WTI) of €42,077 based on the drug-related costs of IFN-β1a SC. The consequent discounted IIs in terms of incremental quality-adjusted survivals versus BSC were: teriflunomide, 0.337 QALYs gained; DMF, 0.314; IFN-β1a SC, 0.264; GA, 0.120; IFN-β1a IM, 0.119; and IFN-β1b SC, –0.239, all with the assumed WTI. The respective incremental time to cane uses were 0.467, 0.428, 0.347, 0.126, 0.166, and –0.436 years, respectively. Consequently, teriflunomide was projected to result in the highest II with the assumed WTI.
      The results of 1-way and multiway sensitivity and subgroup analyses (Table VI) show that the ranking of DMTs in terms of incremental cost-effectiveness appears to be generally robust for sensible changes in modeling assumptions or input variables. The results were sensitive to large changes in the modeled perspective or mixed treatment comparison. As the base case was performed on the basis of a representative population in Finland with characteristics well in line with the indication for teriflunomide, TEMSO trial results on patients’ characteristics and transition probabilities in the placebo group were used in the subgroup analysis. Based on the analysis, the results are also generalizable to an older and more disabled population. Among the 25 modeled DSA scenarios, teriflunomide versus BSC was cost-effective in 72%, 84%, 96%, and 96% of scenarios with WTPs of €25,000, €37,000, €55,000, and €68,000/QALY gained, respectively. DMF versus teriflunomide was cost-effective in 0%, 0%, 4%, and 28% of the 25 DSA scenarios at these respective WTPs.
      Table VIScenario analysis results.
      ParameterDMFTeriflunomideIFN-β1a SCGAIFN-β1a IMBSCIFN-β1b SCICER vs BSC, €/Q gainedICER, €/Q gained
      t€Qst€Qst€Qst€Qst€Qst€Qst€QsDMFTeriflunomideIFN-β1a SCIFN-β1a IMIFN-β1b SCDMF vs Teriflunomide
      Treatment scenario
      Scenarios: 0 = base case; 1 = 0% discounting; 2 = 5% discounting; 3 = British Columbia relapsing–remitting multiple sclerosis (RRMS) Expanded Disability Status Scale (EDSS) transitions57; 4 = relapses from Held et al86; 5 = percentage of hospital relapses from Tampere; 6 = relapse duration 2 mo; 7 = relapse duration 4 mo; 8 = EDSS 7 stopping rule for disease-modifying therapies; 9 = mixed-treatment comparison (MTC): progression and annualized relapse rate (ARR) with low 95% credible interval (CrI); 10 = MTC: progression and ARR with high 95% CrI; 11 = MTC: no year limit, relapses adjusted; 12 = MTC: no year limit; 13 = time with adverse events (AEs) doubled; 14 = time with AEs halved; 15. EDSS-associated costs from Martikainen and Sintonen13; 16 = monitoring costs doubled; 17 = monitoring costs halved; 18 = relapse costs doubled; 19 = relapse costs halved; 20 = AE costs doubled; 21 = AE costs halved; 22 = societal approach14; 23 = EDSS-associated quality of life (QoL) from Kobelt et al10; 24 = similar QoL loss for all relapses; and 25 = TEMSO30,32,33 patient characteristics and placebo transition probabilities for RRMS EDSS.
       03447.813387.723447.593647.483597.463287.334047.0633,68124,08157,690244,105D275,431
       14359.314289.194379.034628.884568.864248.715138.3617,117769037,189200,655D257,611
       22997.022926.952976.843156.743106.722806.613486.3845,20035,48871,757274,356D287,775
       33347.833277.753317.653507.553457.523127.413847.1954,34143,65181,243300,582D2100,644
       43527.733467.643517.513727.393677.373387.234126.9828,83419,96350,325226,293D266,678
       53447.823377.733437.603647.483587.463277.344037.0734,57724,89159,531247,709D276,741
       63447.863387.773447.653647.523597.513287.404047.1134,69224,67760,243256,395D279,476
       73447.763387.663447.543647.433597.403287.274047.0232,72823,51455,345232,940D271,778
       83437.803377.713437.593627.473577.453287.333997.7131,96122,40455,085235,817186,09873,618
       93238.063177.963147.933188.003227.873287.333257.93D1D1D1D1D167,342
       103757.463627.453897.124296.794086.953287.335135.97366,514280,158D2D2D21,784,824
       113337.933277.843417.643487.843557.513287.333787.328303D141,383152,493D262,213
       123447.803357.743357.673427.693537.503287.333577.5033,50417,03119,928146,428165,735160,740
       133447.813387.723447.593647.483597.493287.334047.0633,86724,12857,848261,165D277,031
       143447.813387.723447.593647.483597.463287.334047.0633,58624,05757,610236,352D274,624
       153597.813517.723557.593747.483697.463367.334057.0647,40538,50072,137260,027D286,131
       163477.813417.723467.593677.483627.463287.334077.0639,91631,56867,235266,852D276,220
       173437.813367.723427.593677.483577.463287.334027.0630,56420,33852,918232,732D275,036
       183597.813537.723587.593787.483757.463477.334177.0625,05016,71744,662229,887D261,288
       193377.813307.723367.593577.483517.463197.333977.0637,99727,76364,204251,214D282,502
       203457.813387.723447.593657.483597.463287.334057.0633,98524,13559,752246,942D276,825
       213447.813387.723437.593647.483597.463287.334037.0633,52924,05456,660242,687D274,734
       225637.815597.725697.595947.485887.465617.336467.063760D130,202215,755D245,370
       233446.193386.083445.923645.763595.743285.584045.2126,39318,79645,500189,710D260,137
       243447.873387.783447.653647.533597.533287.414047.1135,30825,20562,785264,278D279,614
       253357.583287.503327.413507.313457.293157.193836.9852,61741,39779,775304,327D2101,341
      Mean3557.763487.683557.553747.453707.413397.284137.0633,14722,60858,452244,916D281,704
      ∆0+10.8–0.04+10.6–0.04+11.2–0.05+10.1–0.03+11.1–0.05+11.0–0.05+9.10.00–535–1473+762+810–43,928+6273
      Δ0 = difference vs base case; BSC = best supportive care; D1 = treatment dominates comparator; D2 = comparator dominates treatment; DMF = dimethyl fumarate; GA = glatiramer acetate; IFN = interferon; ICER = incremental cost-effectiveness ratio; Q = quality-adjusted life-year; QoL =; t€ = cost in thousand Euros.
      low asterisk Scenarios: 0 = base case; 1 = 0% discounting; 2 = 5% discounting; 3 = British Columbia relapsing–remitting multiple sclerosis (RRMS) Expanded Disability Status Scale (EDSS) transitions
      • Palace J.
      • Bregenzer T.
      • Tremlett H.
      • et al.
      UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model.
      ; 4 = relapses from Held et al
      • Held U.
      • Heigenhauser L.
      • Shang C.
      • et al.
      Predictors of relapse rate in MS clinical trials.
      ; 5 = percentage of hospital relapses from Tampere; 6 = relapse duration 2 mo; 7 = relapse duration 4 mo; 8 = EDSS 7 stopping rule for disease-modifying therapies; 9 = mixed-treatment comparison (MTC): progression and annualized relapse rate (ARR) with low 95% credible interval (CrI); 10 = MTC: progression and ARR with high 95% CrI; 11 = MTC: no year limit, relapses adjusted; 12 = MTC: no year limit; 13 = time with adverse events (AEs) doubled; 14 = time with AEs halved; 15. EDSS-associated costs from Martikainen and Sintonen
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      ; 16 = monitoring costs doubled; 17 = monitoring costs halved; 18 = relapse costs doubled; 19 = relapse costs halved; 20 = AE costs doubled; 21 = AE costs halved; 22 = societal approach
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      ; 23 = EDSS-associated quality of life (QoL) from Kobelt et al
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ; 24 = similar QoL loss for all relapses; and 25 = TEMSO
      • Miller A.E.
      • O’Connor P.
      • Wolinsky J.S.
      • et al.
      Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis.
      • O’Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      • O’Connor P.W.
      • Lublin F.D.
      • Wolinsky J.S.
      • et al.
      Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use.
      patient characteristics and placebo transition probabilities for RRMS EDSS.
      For the results of the modeled PSA, see Supplemental Material C in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.01.028. In summary, the PSA results were in line with the deterministic results—teriflunomide dominated injectable first-line DMTs, and DMF had a high mean ICER of 76,803 (2.5%–97.5% percentile, 52,105–139,595; 96% and 75% of ICERs exceeded 55,000 and 68,000, respectively) versus teriflunomide. Teriflunomide had >50% cost-effectiveness probabilities at WTPs of <€77,416/QALY gained versus other first-line DMTs. According to the Bayesian treatment ranking, teriflunomide was the first-best among the DMTs with all unofficial WTP thresholds from Finland mentioned earlier.

      Discussion

      The findings from this modeling study of first-line DMTs for RRMS over 15 years suggest that teriflunomide 14 mg saves costs in comparison with all other reimbursed first-line DMTs in Finland; is cost-effective in comparison with DMF 240 mg at the cited threshold values; dominates injectable first-line DMTs; and, as a complementary result, is associated with the most value gained versus BSC as per the limited DMT-related budget (WTI). In some earlier cost-utility analyses of first-line DMTs for RRMS,
      • Bell C.
      • Graham J.
      • Earnshaw S.
      • et al.
      Cost-effectiveness of four immunomodulatory therapies for relapsing-remitting multiple sclerosis: a Markov model based on long-term clinical data.
      • Dembek C.
      • White L.A.
      • Quach J.
      • et al.
      Cost-effectiveness of injectable disease-modifying therapies for the treatment of relapsing forms of multiple sclerosis in Spain.
      • Imani A.
      • Golestani M.
      Cost-utility analysis of disease-modifying drugs in relapsing-remitting multiple sclerosis in Iran.
      • Jankovic S.M.
      • Kostic M.
      • Radosavljevic M.
      • et al.
      Cost-effectiveness of four immunomodulatory therapies for relapsing-remitting multiple sclerosis: a Markov model based on data a Balkan country in socioeconomic transition.
      • Parkin D.
      • Jacoby A.
      • McNamee P.
      • et al.
      Treatment of multiple sclerosis with interferon beta: an appraisal of cost-effectiveness and quality of life.
      DMTs in comparison with BSC have been found not to be cost-effective based on the commonly cited threshold values—the situation was similar with GA, IFN-β1a IM, and IFN-β1b SC. These outcomes were largely explained by drug prices and clinical parts of the analysis, that is, short-term efficacy and tolerability and long-term efficacy and persistence of treatments.
      The findings from the cost–benefit analysis type IIA based on the WTI seemed to follow the primary outcomes, yet a clear distinction on modeled II for teriflunomide versus BSC in comparison with other DMTs versus BSC was demonstrated with the assumed minimal DMT-related WTI of €42,077/patient. The IIA developed recently is a clinical value-assessment method that could increase clinical interpretation and appeal of the results, and indicate best IIs. However, based on the findings from Soini et al,
      • Soini E.
      • Hautala A.
      • Poikonen E.
      • et al.
      Cost-effectiveness of first-line chronic lymphocytic leukemia treatments when full-dose fludarabine is unsuitable.
      IIA cannot fully substitute the primary cost-effectiveness analysis outcomes if it ignores everything other than drug costs, differences in QoL, differences in AEs, and discounts and mixes the time horizons (ie, costs and benefits are gained from different timelines). Thus, IIA can easily result in investment biases and partial optimization of limited budgets. IIA, as such, probably should not be used as a primary method without acknowledging its limitations—here, the objective of the IIA was only to elaborate and complement the primary outcome based on a clear DMT-related cost and DMT-related II approach. In this study, the IIA was based on a modeling approach capable of synthesizing all of the known evidence. Comprehensive methods and data were needed for a valid IIA.
      In addition to modeling methods, data validity and generalizability can be an issue in decision-analytical modeling. For example, the DEFENSE survey
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      is the most comprehensive, recent, and up-to-date assessment of the MS burden in Finland. However, the results from DEFENSE, as such, should be interpreted with caution. There are various reasons for this: the DEFENSE setting was cross-sectional, with varying patient recall (ie, recall bias can be an issue and there was no link between the cost outcomes and varying recall time, eg, relapses and EDSS-related costs); the base population was limited to active Finnish Neuro Society members, with only 36.9% of invited members participating in the survey (ie, about 10% of the Finnish Neuro Society); EDSS was self-assessed (whereas typically EDSS is assessed by a clinician); the results in patients with RRMS and those with SPMS were not separately reported; the reporting of DMT-related costs in different EDSS classes was unclear; and the adjusted cost (and relapse disutility) results may not have been adequately captured owing to statistical limitations (eg, costs should be assessed with methods that account for both distribution skewness and smearing).
      • Soini E.
      • Leussu M.
      • Hallinen T.
      Administration costs of intravenous biologic drugs for rheumatoid arthritis.
      • Hallinen T.
      • Martikainen J.A.
      • Soini E.J.
      • et al.
      Direct costs of warfarin treatment among patients with atrial fibrillation in a Finnish health care setting.
      Finally, dividing the cost level effect of ≥1 relapse by the mean number of relapses
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      is potentially an inappropriate statistical approach. Instead, the use of, for example, multilevel/hurdle regression or simple semilog regression with relapses as a continuous variable would have produced more reliable results.
      Based on the findings from the extensive sensitivity analyses, the modeled base case results were nonetheless generally robust and generalizable, even when based on the TEMSO trial setting or RRMS transitions from British Columbia, Canada. Because of the potential impact of inherent methodologic issues in the DEFENSE survey,
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      results based on an earlier cost study
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      were used in a sensitivity analysis and demonstrated that the base case analysis was unlikely to overestimate cost differences. The ranking of DMTs in terms of primary outcome appeared to be robust to sensible changes in the input variables.
      Based on the trial evidence, the modeled results of this study are valid. Teriflunomide 14 mg once daily was the only first-line DMT, injectable or oral, to show a significant reduction in both ARR and 3-month risk for disability progression compared with placebo in 2 pivotal clinical trials.
      • O’Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      • Confavreux C.
      • O’Connor P.
      • Comi G.
      • et al.
      Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Compared with placebo, teriflunomide significantly reduced the rate of relapses with neurologic sequelae, relapses leading to hospitalization, and relapses requiring intravenous corticosteroids, and teriflunomide-treated patients spent fewer nights in hospital for relapse.
      • O’Connor P.
      • Wolinsky J.S.
      • Confavreux C.
      • et al.
      Randomized trial of oral teriflunomide for relapsing multiple sclerosis.
      • Miller A.E.
      • Macdonell R.
      • Comi G.
      • et al.
      Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: results from the TOWER study.
      Teriflunomide 14 mg was associated with a significant decrease in the annual rate of all hospitalizations and emergency visits.
      • O’Connor P.W.
      • Lublin F.D.
      • Wolinsky J.S.
      • et al.
      Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use.
      In addition, teriflunomide has a consistent tolerability profile, and AEs reported in patients receiving teriflunomide in clinical trials were largely mild to moderate (diarrhea, nausea, and hair thinning being most common) and infrequently led to treatment discontinuation. Patients reported improved treatment satisfaction with teriflunomide compared with IFN-β1a 44 μg.
      • Vermersch P.
      • Czlonkowska A.
      • Grimaldi L.M.
      • et al.
      Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial.
      Findings from a pooled analysis of data from teriflunomide trials supported the earlier trial findings.
      • Comi G.
      • Freedman M.S.
      • Kappos L.
      • et al.
      Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions.
      Alanine aminotransferase and blood pressure should be monitored regularly, and complete blood cell counts should be performed based on signs and symptoms (eg, infections) during teriflunomide treatment (European Medicines Agency. Teriflunomide [summary of product characteristics] 2013).
      Recently, Teri-PRO (Teriflunomide Patient-Reported Outcomes Study), an international Phase IV real-world study that measured patient-reported outcomes after the initiation of teriflunomide treatment, demonstrated a significant increase in treatment satisfaction in patients who were switched to teriflunomide from other DMTs.
      • Coyle P.
      • Khatri B.
      • Edwards K.
      • et al.
      Teriflunomide real-world safety profile: results of the phase 4 Teri-PRO study.
      • Gold R.
      • Khatri B.
      • Edwards K.
      • et al.
      Impact of teriflunomide treatment on real-world quality of life in the phase 4 Teri-PRO study.
      • Gold R.
      • Khatri B.
      • Edwards K.
      • et al.
      Stable Disability and patient-reported performance outcomes over 48 weeks of teriflunomide treatment: results from the phase 4 Teri-PRO study.
      In that study, a low rate of treatment discontinuation (21.4%) was observed over a 48-week period,
      • Coyle P.
      • Khatri B.
      • Edwards K.
      • et al.
      Teriflunomide real-world safety profile: results of the phase 4 Teri-PRO study.
      which is consistent with the findings from the present modeling study, with those from teriflunomide clinical trials, and with those from other recent real-world studies.
      • Moisset X.
      • Zuel M.
      • Conde S.
      • et al.
      Teriflunomide and dimethylfumarate: prescription and patients’ satisfaction in a real life setting.
      • Guger M.
      • Enzinger C.
      • Leutmezer F.
      • et al.
      Real Life Use of natalizumab, fingolimod, dimethylfumarate, teriflunomide and alemtuzumab in Austria: benefit-risk data from the Austrian Multiple Sclerosis Treatment Registry.
      • Annovazzi P.
      • Mallucci G.
      • Lo Re M.
      • et al.
      Real life efficacy and tolerability of teriflunomide: a multicentre study.
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      In Teri-PRO, statistically significant improvements were also seen in QoL (as measured by the MS International QoL scale), particularly on the subscales of activities of daily living, psychological well-being, symptoms, and coping.
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      Impact of teriflunomide treatment on real-world quality of life in the phase 4 Teri-PRO study.
      In addition, teriflunomide seems to have some benefit in patients who are switched from natalizumab due to a risk for progressive multifocal leukoencephalopathy.
      • Cohan S.L.
      • Edwards K.
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      • Edwards K.
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      Evaluation of switching to teriflunomide in high risk natalizumab patients.
      However, it is important to note that the risk for progressive multifocal leukoencephalopathy, a severe AE that is included in the DMF labeling in Europe

      European Medicines Agency. Dimethyl fumarate [summary of product characteristics]. 2014.

      and the United States,

      US Food and Drug Administration. Dimethyl fumarate [prescribing information]. 2016.

      was not included in the present modeling study.
      On the other hand, injection-site or skin reactions, influenza-like symptoms, and neutralizing antibodies are common AEs associated with injectable DMTs and are among the most common reasons for discontinuing injectable DMTs.
      • Soini E.
      • Holmberg M.
      • Asseberg C.
      • Sumelahti M.L.
      Modelling the persistence of disease-modifying drug treatment (DMT) and its independent drivers in Finnish multiple sclerosis (MS) patients: parametric survival modelling.
      • Walther E.U.
      • Hohlfeld R.
      Multiple sclerosis: side effects of interferon beta therapy and their management.
      Flushing, hot flushes, and upper gastrointestinal symptoms are the AEs most commonly reported with DMF therapy, according to an assessment by the National Institute for Health and Care Excellence.
      National Institute for Health and Care Excellence (NICE)
      Dimethyl fumarate for treating relapsing-remitting multiple sclerosis. NICE technology appraisal guidance 320.
      Based on real-world evidence, AEs relating to DMF therapy can more frequently result in treatment discontinuation in comparison with teriflunomide
      • Moisset X.
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      Teriflunomide and dimethylfumarate: prescription and patients’ satisfaction in a real life setting.
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      Real Life Use of natalizumab, fingolimod, dimethylfumarate, teriflunomide and alemtuzumab in Austria: benefit-risk data from the Austrian Multiple Sclerosis Treatment Registry.
      —an observation not accounted for in the present study; in fact, the modeling assumed a lesser withdrawal rate in DMF users compared with teriflunomide users.
      Among earlier cost-effectiveness studies of first-line MS DMTs,
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      • Zhang X.
      • Hay J.W.
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      Cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate and intramuscular interferon-beta1a in relapsing-remitting multiple sclerosis.
      only 1 includes oral DMTs (DMF, teriflunomide, US setting).
      • Zhang X.
      • Hay J.W.
      • Niu X.
      Cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate and intramuscular interferon-beta1a in relapsing-remitting multiple sclerosis.
      In the present modeling study, teriflunomide 14 mg and DMF 240 mg were cost-effective treatments versus BSC at the WTP threshold values of €37,000 or €55,000/QALY gained. However, at the most plausible WTP of €25,000/QALY gained versus BSC, only teriflunomide 14 mg was cost-effective. Furthermore, DMF 240 mg was not cost-effective versus teriflunomide 14 mg at Finland’s unofficial WTP threshold values.
      Overall health care efficiency, low drug prices, and costly health care resources may be reasons behind the results from the present analysis. However, the health care setting in Finland can be regarded as a robust default setting and as a benchmark for health economic assessments for many reasons. Most important, the productivity and efficiency of the Nordic health care systems are high, as demonstrated in multiple studies of the health care system in Finland.
      • Häkkinen U.
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      Social security code and national registries cover all citizens in Finland, and one of the most advanced biobank laws is in use for the willing. Furthermore, Finland has a low pharmacy purchase price for reimbursed drugs
      • Hallinen T.
      • Soini E.
      The impact of the pharmaceutical pricing system on cost-effectiveness results: Finnish analysis.
      among European countries, and tendering or patient access schemes have not been possible for reimbursed drugs,
      • Nyblin K.
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      eliminating uncertainties about drug prices in Finland. Finland also has national lists for health care unit costs
      • Hujanen T.
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      and official indexes based on national statistics.
      Statistics Finland
      Price Index for Public Expenditures.

      Statistics Finland. Income index. Helsinki: Statistics Finland; 2016.

      In some countries, such information does not exist. Currently, Finland is undergoing health care, social welfare, and regional government reform,
      Ministry of Social Affairs and Health, Ministry of Finance
      Healthcare, social welfare and regional government reform package.
      which is likely to result in digitized service solutions for the primary (eg, benchmarking service producers) and secondary (eg, market access to new drugs and devices) uses of national, areal, local, and biobank health care and social welfare data in terms of effectiveness and cost-effectiveness.
      • Soini E.
      Expert solutions in outcomes research. Legal Working Group Workshop, Secondary Use of Data: Information Management, Control and Monitoring [in Finnish].
      Furthermore, the Finnish parliament recently received a proposal for a risk-sharing scheme centered around an agreement-based conditional reimbursement from the government of Finland. However, the official wholesale price in the application would still need to be affordable, and the risk-sharing scheme would be available only through the optional application process.
      • Pelkonen L.
      Conditional Reimbursement [in Finnish].

      Riksdag Parliament. Government proposal 184/2016 vp [in Swedish]. 2016.

      This development has the potential to further increase the efficiency of Finland’s health care system and the relevance of modeling-based health economic assessments. Finally, Finland’s guidance for health economic analyses
      Pharmaceuticals Pricing Board
      Composing health economic evaluation for the pricing and reimbursement application.
      is well in line with many other cost-effectiveness analysis guidelines.
      National Institute for Health and Care Excellence (NICE)
      Guide to the Methods of Technology Appraisal 2013.
      Belgian Health Care Knowledge Centre
      Belgian Guidelines for Economic Evaluations and Budget Impact Analyses.
      College of Health Economists
      French guidelines for the economic evaluation of health care technologies [in French].
      Health Care Insurance Board
      Guidelines for pharmacoeconomic research, updated version [in Dutch].
      Health Information and Quality Authority
      Guidelines for the economic evaluation of health technologies in Ireland.
      Institute for Pharmaceutical Research
      Guidelines on Health Economic Evaluation [in German].

      Baltic guideline for economic evaluation of pharmaceuticals (pharmacoeconomic analysis). Latvia, Estonia and Lithuania: 8 August 2002. International Society for Pharmacoeconomics and Outcomes Research; 2002:1--6.

      • López-Bastida J.
      • Oliva J.
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      • et al.
      Spanish recommendations on economic evaluation of health technologies.
      Norwegian Medicines Agency
      Guidelines on How To Conduct Pharmacoeconomic Analyses [in Norwegian].
      Scottish Medicines Consortium
      Guidance to Manufacturers for Completion of New Product Assessment Form.
      Health economic modeling is needed to handle the multidimensional assessment challenge, to summarize the trial evidence and local input data, to enable extrapolations and discounting, and to produce results in terms of generalizable outcomes with standard interpretation. In the future, it will be necessary to assess the effects of the risk-sharing scheme with some treatments. Thus, by necessity, health economic models are simplifications of a very complicated reality. Here, these assumptions are discussed.
      In the model, potential treatment sequences were excluded, and switching between different DMTs was not accounted for. However, dropping out of first-line DMT altogether was included. To analyze the cost-utility of first-line RRMS DMTs, a sequential approach was not needed. A sequential approach would be more viable in later treatment line assessment or in health technology assessment searching for the optimal treatment sequence. Furthermore, there was no gold standard treatment sequence based on Finnish data, and the treatment of patients with RRMS seemed to be guided by per-patient decisions (which are probably affected by disease severity, disease progression, patient/clinician preferences, and potential DMT-related AEs).
      In the selected modeling approach, all DMTs compared were handled equally by assuming similar treatment after the first-line DMT, and the result was not jeopardized by inherent and potentially problematic assumptions related to second- and later-line DMT efficacy, tolerability, and washout. Furthermore, in a sequential model, the result may be confounded by potential population changes between the treatment lines. In the present analysis, the results were directly related to differences due to the first-line DMT. In the evaluation, the first-line DMTs were being compared against each other, which potentially was associated with less uncertainty and fewer assumptions, and also in reduced bias and confounding in comparison with a sequential approach relying on multiple additional assumptions due to lack of data. Furthermore, all of the DMTs in the comparison were pharmacy prescription drugs, which overcomes issues of comparing intravenously administered hospital drugs (eg, further-line or high-activity MS treatments) and pharmacy prescription drugs
      • Hallinen T.
      • Soini E.
      The impact of the pharmaceutical pricing system on cost-effectiveness results: Finnish analysis.
      • Soini E.
      • Leussu M.
      • Hallinen T.
      Administration costs of intravenous biologic drugs for rheumatoid arthritis.
      and are currently subject to public reimbursement in Finland.
      In earlier cost-effectiveness analyses of treatments for diseases other than MS, if the treatment sequence included treatment options that were not the most cost-effective, the incremental cost-effectiveness of the sequence deteriorated in comparison with base treatments.
      • Hallinen T.A.
      • Soini E.J.
      • Eklund K.
      • Puolakka K.
      Cost-utility of different treatment strategies after the failure of tumour necrosis factor inhibitor in rheumatoid arthritis in the Finnish setting.
      • Soini E.
      • Martikainen J.A.
      • Nousiainen T.
      Treatment of follicular non-Hodgkin’s lymphoma with or without rituximab: cost-effectiveness and value of information based on a 5-year follow-up.
      • Soini E.
      • Hallinen T.
      • Kauppi M.
      • et al.
      Comprehensive health economic assessment of sequenced treatment with biologics in moderate-to-severe rheumatoid arthritis: analysis based on ACR50 and ACR70 responses.
      • Soini E.
      • Martikainen J.A.
      • Vihervaara V.
      • et al.
      Economic evaluation of sequential treatments for follicular non-Hodgkin lymphoma.
      First-line MS DMTs lacked published cost-utility evidence; thus, there are no supporting publications to benchmark or determine the optimal MS treatment sequence. Furthermore, in these situations, it was more important to know how DMTs perform in comparison with the minimum case (BSC). Based on the Finnish MS research registry data, only a percentage of patients with RRMS are currently actively treated. This may be for reasons connected with efficacy, tolerability, the patient, or the clinician.
      Based on the Finnish MS research registry data, MS DMT-related AEs seem to accumulate in some patients. However, owing to the similarity of some AEs produced by frequently used first-line MS injectable DMTs, it is uncertain whether AEs occur in some patients after changing from one first-line DMT to another. Furthermore, no well-controlled research evidence exists demonstrating the clinical gains or benefits of switching the first-line DMT.
      EDSS transitions in this modeled evaluation were based on data from Finland (RRMS) and London, Ontario, Canada (SPMS),
      • Weinshenker B.G.
      • Bass B.
      • Rice G.P.
      • et al.
      The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.
      because these were most comprehensive for the setting and because they included survival data and were recorded and checked by clinical experts. Other examples of EDSS data include the British Columbia database,
      • Palace J.
      • Bregenzer T.
      • Tremlett H.
      • et al.
      UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model.
      • Palace J.
      • Duddy M.
      • Bregenzer T.
      • et al.
      Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator.
      • Shirani A.
      • Zhao Y.
      • Kingwell E.
      • et al.
      Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975-2009).
      • Tremlett H.
      • Zhao Y.
      • Devonshire V.
      Natural history comparisons of primary and secondary progressive multiple sclerosis reveals differences and similarities.
      the Lyon MS Cohort,
      • Confavreux C.
      • Vukusic S.
      • Adeleine P.
      Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process.
      the Rennes MS Database,
      • Leray E.
      • Yaouanq J.
      • Le Page E.
      • et al.
      Evidence for a two-stage disability progression in multiple sclerosis.
      and the Sonya Slifka Longitudinal MS Study.
      • Minden S.L.
      • Frankel D.
      • Hadden L.
      • et al.
      The Sonya Slifka longitudinal multiple sclerosis study: methods and sample characteristics.
      The effects of RRMS EDSS transitions were tested in sensitivity analyses, and the relative results remained unchanged. In fact, the recently published RRMS transitions from British Columbia, Canada
      • Palace J.
      • Bregenzer T.
      • Tremlett H.
      • et al.
      UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model.
      agree with those from Finland.
      Last, in addition to clinical real-world evidence, future real-world studies should collect real-world data to support modeled economic evaluations. They should, accordingly, include comprehensive assessments of the EDSS specified separately for RRMS; SPMS and primary progressive MS; relapses; AEs and withdrawals; comorbidities; patient income; and the impact of these outcomes on resource use, costs, QoL, and mortality. This real-world evidence may be obtainable using structural treatment-monitoring systems and long-term registry data with sufficient data coverage and could enable the use of event-based or microsimulation methods in the assessments. In addition, IIA type analysis should be used to increase the clinical appeal of complex analyses.

      Conclusions

      Data presented from the present modeling study highlight the cost-effectiveness of teriflunomide 14 mg once daily compared with DMF 240 mg BID when the commonly cited threshold values are taken into account. In the present modeling study, teriflunomide 14 mg also dominated all other commonly used first-line DMTs for RRMS in Finland and was associated with the highest II.

      Conflicts of Interest

      This research and editorial support was funded by Sanofi Genzyme, Helsinki, Finland. Sanofi Genzyme participated in the study design; collection, analysis, and interpretation of data; writing of the manuscript; and the decision to submit the article for publication.
      E. Soini is a founding partner and employee of ESiOR Oy, Kuopio, Finland. ESiOR Oy carries out studies, statistical analysis, consultancy, education, reporting and health economic evaluations for several pharmaceutical, food industry, diagnostics and device companies; hospitals; consultancies; and academic institutions. J. Joutseno is employed by Genzyme, a Sanofi Company, Helsinki, Finland. M.-L. Sumelahti has been a consultant and member of advisory councils at Genzyme, Novartis, and Biogen, and has received a travel grant from Novartis.

      Acknowledgments

      E. Soini is grateful to Taru Hallinen, ESiOR Oy, for helpful comments on an early manuscript draft. Editorial support in the preparation of the manuscript was provided by Hannah Greenwood, Fishawack Communications.
      Authorship criteria: study management, E. Soini and J. Joutseno; concept/design and study/analysis plan, E. Soini, M.-L. Sumelahti, and J. Joutseno; data assembly, E. Soini, M.-L. Sumelahti, and J. Joutseno; analysis, E. Soini; manuscript drafting, E. Soini; critical manuscript revision, E. Soini, M.-L. Sumelahti, and J. Joutseno; all authors gave final approval for the version to be published. All authorship decisions were made on the basis of scientific consideration.

      Appendix A. Supplementary material

      Supplement A. EDSS-based RRMS and SPMS transition matrices

      EDSS
      Finnish Medical Society Duodecim, Finnish Neurological Society Working Group
      MS Disease.
      is the key outcome in the assessment of MS disability progression. In the Finnish Pirkanmaa-Seinäjoki-Vaasa MS registry, there were 1359 patients with MS with EDSS assessment data available, with altogether 2458 measurements. These patients were identified from administrative registries. The data collection, case ascertainment procedure, and ethical permits have been described in detail elsewhere.
      • Pugliatti M.
      • Rosati G.
      • Carton H.
      • et al.
      The epidemiology of multiple sclerosis in Europe.
      World Health Organization
      Atlas multiple sclerosis resources in the world 2008.
      Incident MS cases diagnosed in the study region that fulfilled the McDonald
      • Holmberg M.
      • Murtonen A.
      • Elovaara I.
      • Sumelahti M.L.
      Increased female MS incidence and differences in gender-specific risk in medium- and high-risk regions in Finland from 1981-2010.
      criteria were included. The classification of disease course to RRMS was performed using standardized definitions.
      • Sumelahti M.L.
      • Tienari P.J.
      • Hakama M.
      • Wikstrom J.
      Multiple sclerosis in Finland: incidence trends and differences in relapsing remitting and primary progressive disease courses.
      A total of 1242 patients had RRMS, and these patients with RRMS had altogether 2299 EDSS measurements between August 27, 1986, and December 31, 2010. Women accounted for 69.8% of the patients. In all, 62.2% of the EDSS assessments were carried out at the beginning of a DMT episode with an EDSS score of 0–7. In 2010, EDSS values were assessed for all patients alive (July 1, 2010, assumed, if no specific day shown in the data).

      EDSS Transitions in RRMS

      Figure A.1 shows all EDSS measurements over time for descriptive purposes. As can be seen, most EDSS measurements were performed for patients with RRMS (green colored dots). The figure also shows that there was censoring in the EDSS measurements in EDSS classes 6.5–9.5.
      Figure A.1.
      Figure A.1All EDSS measurements (jittered to prevent over-plotting) over time, by MS type (RRMS, green; PPMS, red; SPMS, blue). EDSS = Expanded Disability Status Scale; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis.
      For descriptive purposes, combined Figure A.2 shows the development from one EDSS measurement to the next among patients with RRMS, conditional on particular EDSS scores.
      Figure A.2.
      Figure A.2EDSS development in RRMS population over time showing next EDSS scores. The blue line gives the average expected EDSS over time and the shaded area is the 95% CI obtained by unadjusted local polynomial smoothing of the raw data. CI = confidence interval; EDSS = Expanded Disability Status Scale; RRMS = relapsing-remitting multiple sclerosis.
      EDSS development over time needs to be modeled in order to estimate the progression of MS. MS progression for the model was estimated using integer RRMS EDSS scores (halves rounded up; 9.5 assumed to be 9.0 because the patient is alive when EDSS is 9.5). The JAGS software V3.3.0,
      • Sumelahti M.L.
      • Tienari P.J.
      • Wikstrom J.
      • et al.
      Regional and temporal variation in the incidence of multiple sclerosis in Finland 1979-1993.
      which is a statistical program capable of analyzing Bayesian hierarchical models by Markov Chain Monte Carlo (MCMC) simulation methods, was used to estimate the EDSS transition probabilities.
      When estimating the RRMS EDSS 0–9 transitions, uniform priors were assumed because no earlier Finnish transition probabilities data were available. Based on a prior knowledge of the data in question, 60% of the mortality was assumed to be MS-related.
      • Sumelahti M.L.
      • Tienari P.J.
      • Wikstrom J.
      • et al.
      Increasing prevalence of multiple sclerosis in Finland.
      This estimate was conservative in comparison to other estimates, which have a higher proportion of MS-related mortality (eg, 78.3% in Goodin et al
      • Brunet D.G.
      • Hopman W.M.
      • Singer M.A.
      • et al.
      Measurement of health-related quality of life in multiple sclerosis patients.
      ). The results shown in Table A.I are well in line with the recent British Columbia results.
      • Karampampa K.
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      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      Table A.IAnnual transition probability matrix by EDSS for patients with RRMS based on the Finnish data.
      From/ToRRMS EDSS 0RRMS EDSS 1RRMS EDSS 2RRMS EDSS 3RRMS EDSS 4RRMS EDSS 5RRMS EDSS 6RRMS EDSS 7RRMS EDSS 8RRMS EDSS 9RRMS EDSS 10
      RRMS EDSS 00.678220.263140.042750.011360.003640.000770.000030.000030.000030.000030.00000
      RRMS EDSS 10.112990.607110.179220.064840.027250.007110.000370.000370.000370.000370.00000
      RRMS EDSS 20.017700.173120.375210.227120.142630.049600.003650.003650.003650.003650.00001
      RRMS EDSS 30.005470.072820.265420.256900.240070.110650.012160.012160.012160.012160.00002
      RRMS EDSS 40.001550.027100.147720.212890.300970.182100.031890.031890.031890.031890.00009
      RRMS EDSS 50.000450.009810.071240.136070.252040.209690.080100.080100.080100.080100.00031
      RRMS EDSS 60.000010.000270.002760.007860.023140.041730.230710.230710.230710.230710.00141
      RRMS EDSS 70.000010.000270.002760.007860.023140.041730.230710.230710.230710.230710.00141
      RRMS EDSS 80.000010.000270.002760.007860.023140.041730.230710.230710.230710.230710.00141
      RRMS EDSS 90.000010.000270.002760.007860.023140.041730.230710.230710.230710.230710.00141
      RRMS EDSS 100.000000.000000.000000.000000.000000.000000.000000.000000.000000.000001.00000

      RRMS to SPMS Transition

      The hazard rate (HR, λ) for conversion from RRMS EDSS 1 to SPMS was calculated assuming an exponential survival function (ie, a constant hazard of converting to SPMS over time):
      S(t)=exp(λt)


      λ for an exponential distribution could be estimated from the median time of conversion to SPMS, reported to be 15 years based on London Ontario data,
      • Kobelt G.
      • Berg J.
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      Treatment costs and quality of life losses.
      ie:
      λ=ln(2)/15


      This gives an annual HR of 0.0462 for SPMS-conversion of patients in EDSS 1.
      The Finnish dataset includes only a few observations of conversion to SPMS, and an EDSS-specific rate could not be estimated from these. Based on the London Ontario data, the Cox proportional hazards model was:
      H(t)=H(t)EDSS1.exp(βX)


      where H(t) is the HR of conversion for any EDSS state; H(t)EDDS1, the HR of conversion for EDDS 1; and β, the coefficient (0.25270) of the relationship between EDSS and the HR of progression between the base case EDSS 1 and all other EDSS states.
      • Kobelt G.
      • Berg J.
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      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      • Martikainen J.
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      Treatment costs and quality of life losses.
      Using Bender et al,
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      the relationship was reformulated as:
      ln[H(t)H(t)EDSS1]=β.X


      Thus:
      H(t)=λ.eβ.X


      This was used to derive the HR of conversion from EDSS 1 through each successive stage to EDSS 8 (Table A.II). All estimated HRs were then subsequently converted into probabilities
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      :
      p=1exp(rt)


      Table A.IIAnnual probabilities of conversion to SPMS from RRMS by EDSS score.
      EDSS scoreCalculationHazard rate of conversionCalculationProbability
      1ln(2)/150.0462101-exp(-0.046210)0.045158
      20.04621*e ^(0.25270*2)0.0766001-exp(-0.076600)0.073739
      30.04621*e ^(0.25270*3)0.0986221-exp(-0.098622)0.093915
      40.04621*e ^(0.25270*4)0.1269751-exp(-0.126975)0.119245
      50.04621*e ^(0.25270*5)0.1634801-exp(-0.163480)0.150817
      60.04621*e ^(0.25270*6)0.2104801-exp(-0.210480)0.189805
      70.04621*e ^(0.25270*7)0.2709931-exp(-0.270993)0.237378
      80.04621*e ^(0.25270*8)0.3489021-exp(-0.348902)0.294538
      9
      Information for EDSS 9 was not available from the London Ontario dataset. Thus, a 100% conversion rate for patients with RRMS in EDSS 9 was assumed.
      1.000000
      100.000000
      Information for EDSS 9 was not available from the London Ontario dataset. Thus, a 100% conversion rate for patients with RRMS in EDSS 9 was assumed.

      EDSS Transitions in SPMS

      For SPMS transitions, data from the London Ontario MS registry
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      were available and used (Table A.III), because the Finnish register data had too few EDSS measurements for patients with SPMS.
      Table A.IIIAnnual transition probability matrix by EDSS for patients with SPMS based on London Ontario data.
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      From/ToSPMS EDSS 0SPMS EDSS 1SPMS EDSS 2SPMS EDSS 3SPMS EDSS 4SPMS EDSS 5SPMS EDSS 6SPMS EDSS 7SPMS EDSS 8SPMS EDSS 9SPMS EDSS 10
      SPMS EDSS 01.0000.0000.0000.0000.0000.0000.0000.0000.0000.0000.000
      SPMS EDSS 10.0001.0000.0000.0000.0000.0000.0000.0000.0000.0000.000
      SPMS EDSS 20.0000.0000.4550.3750.0990.0410.0270.0020.0010.0000.000
      SPMS EDSS 30.0000.0000.0000.5630.2800.0880.0610.0050.0020.0000.000
      SPMS EDSS 40.0000.0000.0000.0000.4820.2810.2180.0130.0060.0000.000
      SPMS EDSS 50.0000.0000.0000.0000.0000.3400.5970.0410.0230.0000.000
      SPMS EDSS 60.0000.0000.0000.0000.0000.0000.8700.0810.0480.0000.000
      SPMS EDSS 70.0000.0000.0000.0000.0000.0000.0000.6450.3490.0060.000
      SPMS EDSS 80.0000.0000.0000.0000.0000.0000.0000.0000.9920.0080.000
      SPMS EDSS 90.0000.0000.0000.0000.0000.0000.0000.0000.0001.0000.000
      SPMS EDSS 100.0000.0000.0000.0000.0000.0000.0000.0000.0000.0001.000

      References

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        Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452.
      • 2.
        Holmberg M, Murtonen A, Elovaara I, Sumelahti ML. Increased female MS incidence and differences in gender-specific risk in medium- and high-risk regions in Finland from 1981-2010. Multiple sclerosis international. 2013;2013:182516.
      • 3.
        Sumelahti ML, Holmberg MH, Murtonen A, Huhtala H, Elovaara I. Increasing incidence in relapsing-remitting MS and high rates among young women in Finland: A thirty-year follow-up. Multiple sclerosis international. 2014;2014:186950.
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        McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of neurology. 2001;50:121-127.
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        Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46:907-911.
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        Plummer M. JAGS: A program for analysis of Bayesian graphical modeals using Gibbs sampling. 3rd International Workshop on Distributed Statistical Computing (DSC 2003). Vienna, Austria: DSC; 2003.
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        Sumelahti ML, Hakama M, Elovaara I, Pukkala E. Causes of death among patients with multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2010;16:1437-1442.
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        Goodin DS, Ebers GC, Cutter G, et al. Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNbeta-1b study. BMJ open. 2012;2.
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        Palace J, Bregenzer T, Tremlett H, et al. UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model. BMJ open. 2014;4:e004073.
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        Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain : a journal of neurology. 1989;112 ( Pt 1):133-146.
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        Bender R, Augustin T, Blettner M. Generating survival times to simulate Cox proportional hazards models. Statistics in medicine. 2005;24:1713-1723.
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        Fleurence RL, Hollenbeak CS. Rates and probabilities in economic modelling: transformation, translation and appropriate application. PharmacoEconomics. 2007;25:3-6.
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        Sanofi Genzyme Data on File. London Ontario MS registry data. 2016.

      Supplement B. AEs: Incidence, Treatment Costs, and Disutilities

      Risks of AEs

      Adverse events (AEs) were included to the modeling based on a ≥4% difference between active treatment and placebo and/or clear inclusion in a previous NICE HTA submission (Table B.I). Nearly all AEs related to DMF, GA, interferons, and teriflunomide are mild to moderate and of short duration. The reason for not including the AEs with a <4% difference between placebo and active treatment and no NICE HTA reference was to simplify the analysis. Recently, the FDA added a progressive multifocal leukoencephalopathy (PML, a very severe AE) scenario to the DMF label. However, possible PML risk with DMF was ignored owing to uncertainty related to exact PML risk (usually PML risk accumulates over time).
      Table B.IAnnualized risk of AEs associated with treatment.
      TreatmentAdverse event (AE)Annualized probabilityRate source
      DMF 240 mg (Tecfidera®)Flushing19.0%Aggregate weighted estimate based on the trials referred to in the HTA submission (NICE)
      • Pugliatti M.
      • Rosati G.
      • Carton H.
      • et al.
      The epidemiology of multiple sclerosis in Europe.
      Nausea6.2%
      Upper abdominal pain5.1%
      Vomiting4.3%
      Hot flush3.4%
      GA 20 mg (Copaxone®)Injection-site reaction68.4%Johnson et al
      World Health Organization
      Atlas multiple sclerosis resources in the world 2008.
      Dyspnea6.6%
      Chest pain, flushing2.8%
      Palpitation2.4%
      IFNβ-1a-SC 44 µg (Rebif®)Injection-site reaction38.3%PRISMS Study Group
      • Holmberg M.
      • Murtonen A.
      • Elovaara I.
      • Sumelahti M.L.
      Increased female MS incidence and differences in gender-specific risk in medium- and high-risk regions in Finland from 1981-2010.
      Myalgia7.0%
      Neutralizing antibodies6.5%
      Fever6.1%
      IFNβ-1a-IM 30 µg (Avonex®)Headache42.6%Jacobs et al
      • Sumelahti M.L.
      • Tienari P.J.
      • Hakama M.
      • Wikstrom J.
      Multiple sclerosis in Finland: incidence trends and differences in relapsing remitting and primary progressive disease courses.
      Influenza-like symptoms37.4%
      Muscle pain18.5%
      Nausea16.9%
      Neutralizing antibodies14.0% year 1, 8.0% year 2+
      Fever12.5%
      Asthenia11.1%
      Chills11.1%
      Diarrhea8.3%
      IFNβ-1b 250 µg (Betaferon®)Injection-site reaction80.0% year 1, 44.0% year 2+IFNB Multiple Sclerosis Study Group
      • Sumelahti M.L.
      • Tienari P.J.
      • Wikstrom J.
      • et al.
      Regional and temporal variation in the incidence of multiple sclerosis in Finland 1979-1993.
      Neutralizing antibodies27.4% year 1, 5.6% year 2+
      Influenza-like symptoms8.0% year 1, 5.5% year 2+
      Teriflunomide 14 mg (Aubagio®)Diarrhea9.1%O’Connor et al
      • Sumelahti M.L.
      • Tienari P.J.
      • Wikstrom J.
      • et al.
      Increasing prevalence of multiple sclerosis in Finland.
      Nausea6.9%
      Hair thinning6.6%
      In order to convert risk of AEs from studies to annualized risk of AEs, the risk of AEs was converted to a rate using a standard formula,
      Finnish Medical Society Duodecim, Finnish Neurological Society Working Group
      MS Disease.
      and the resulting annualized AE rates were then converted back to annualized probabilities/risks (Table B.I).
      AEs were assumed to occur at most once per cycle. However, injection-site reaction, fever, and nausea tend to occur after every interferon dose, and chest pain, palpitation, and dyspnea may happen after every GA dose for subjects who have a particular AE. Consequently, the impact of those AEs may be underestimated for interferons and GA.

      Treatment of AEs

      In Finnish practice, the active treatment of severe AEs takes place in the neurology unit, and moderate AEs result in phone calls to the neurologic department. More severe AEs, including injection-site reactions, chest pain, palpitation, dyspnea, hot flush, and vomiting, require specialist consultation (Table B.II). Chest pain and flushing, palpitation, and dyspnea related to GA are usually transient.
      • Brunet D.G.
      • Hopman W.M.
      • Singer M.A.
      • et al.
      Measurement of health-related quality of life in multiple sclerosis patients.
      Asthenia, chills, diarrhea, flush, hair thinning, and nausea alone do not usually need active treatment; thus, phone contact to the neurologic department was assumed for these. Conservatively, none of the AEs included were assumed to result in hospitalization.
      Table B.IIResource use and costs (€) associated with AE management.
      Adverse event (AE)Cost (€)Resources (original unit cost and source)
      Asthenia, chills, diarrhea, flush, hair thinning, or nausea24.43Phone call (€24.43
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      )
      Upper abdominal pain30.73Phone call (€24.43
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ) + blood test taking (€5.47
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • et al.
      Modeling the cost-effectiveness of a new treatment for MS (natalizumab) compared with current standard practice in Sweden.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ) + LFT (€1.00
      • Kobelt G.
      • Kasteng F.
      Access to Innovative Treatments in Multiple Sclerosis in Europe.
      )
      Fever, headache, influenza symptoms, muscle pain, or myalgia35.18Phone call (€24.43
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ) + NSAID (ibuprofen 600mg €10.74
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      )
      Chest pain, flushing, dyspnea, injection-site reaction, palpitation, or vomiting340.76Specialist visit (€340.76 incl. 5% copayment
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      )
      Hot flush358.12Specialist visit (€340.76 incl. 5% copayment
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ) + antihistamine (desloratadine 5 mg €17.36
      • Martikainen J.
      • Sintonen H.
      Treatment costs and quality of life losses.
      )
      Neutralizing antibodies438.74Specialist visit (€340.76 incl. 5% co-payment
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ) + blood test taking (€5.47
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • et al.
      Modeling the cost-effectiveness of a new treatment for MS (natalizumab) compared with current standard practice in Sweden.
      at 2014 values
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ) + antibody test (€92.50
      • Ruutiainen J.
      • Viita A.M.
      • Hahl J.
      • et al.
      Burden of illness in multiple sclerosis (DEFENSE) study: the costs and quality-of-life of Finnish patients with multiple sclerosis.
      )
      Ibuprofen is used to treat fever, headache, influenza, muscle pain, and myalgia. Antihistamine is used to treat (at minimum) the hot flush associated with DMF. No other drugs were assumed to be used for the treatment of DMT-related AEs.

      QoL Loss of AEs

      Resource use and costs associated with AE management are given in Table B.II, and QoL losses and durations associated with AEs are given in Table B.III.
      Table B.IIIQuality of life (QoL) loss and its duration associated with AEs.
      Adverse event (AE)QoL lossDurationAssumptionDisutility source
      Flushing, hair thinning, neutralizing antibodies, or upper abdominal pain−0.00011 year
      Expert opinion.
      Assumption
      Headache−0.08272 days
      Expert opinion.
      Soini and Hallinen
      • Sillanpaa M.
      • Andlin-Sobocki P.
      • Lonnqvist J.
      Costs of brain disorders in Finland.
      Injection-site reaction24 hours
      Expert opinion.
      Headache
      Muscle pain or myalgia1 week
      Expert opinion.
      Diarrhea−0.10342.5 days
      • Valjakka S.
      • Nurmi-Koikkalainen P.
      • Anttila H.
      • Konttinen J.
      Asthenia or chills1 week
      Expert opinion.
      Diarrhea
      Fever24 hours
      Expert opinion.
      Influenza-like symptoms1 week
      • Sumelahti M.L.
      • Hakama M.
      • Elovaara I.
      • Pukkala E.
      Causes of death among patients with multiple sclerosis.
      Vomiting3 weeks
      Expert opinion.
      Nausea1 week
      Expert opinion.
      Chest pain, flushing, dyspnea, or palpitation−0.124424 hours
      • Brunet D.G.
      • Hopman W.M.
      • Singer M.A.
      • et al.
      Measurement of health-related quality of life in multiple sclerosis patients.
      Somnolence
      Hot flush3 weeks
      Expert opinion.
      low asterisk Expert opinion.

      References

      • 1.
        Fleurence RL, Hollenbeak CS. Rates and probabilities in economic modelling: transformation, translation and appropriate application. PharmacoEconomics. 2007;25:3-6.
      • 2.
        National Institute for Health and Care Excellence. Dimethyl fumarate for treating relapsing-remitting multiple sclerosis. NICE technology appraisal guidance 320. London: National Institute for Health and Care Excellence; 2014.
      • 3.
        Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268-1276.
      • 4.
        PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet (London, England). 1998;352:1498-1504.
      • 5.
        Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Annals of neurology. 1996;39:285-294.
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        IFNB Multiple Sclerosis Study Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277-1285.
      • 7.
        O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. The New England journal of medicine. 2011;365:1293-1303.
      • 8.
        Finnish Medical Society Duodecim, Finnish Neurological Society Working Group. MS Disease. Current Care Criteria. Helsinki: Current Care; 2015.
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        Kapiainen S, Väisänen A, Haula T. Health and social care costs in year 2011 in Finland. Helsinki, Finland. Helsinki: Terveyden ja hyvinvoinnin laitos; 2014.
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        Statistics Finland. Price index for public expenditures. Helsinki: Statistics Finland; 2016.
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        Hujanen T, Kapiainen S, Tuominen U, Pekurinen M. Health care unit costs in year 2006 in Finland. Helsinki: Stakesin Työpapereita; 2008.
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        FimLab. Pricelist for laboratory tests. Tampere: FimLab; 2013.
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        Pharmaceuticals Pricing Board. Reimbursable of Authorized Medicinal Products [in Finnish]. Helsinki: Pharmaceuticals Pricing Board; 2016.
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        Hospital Tampere University. Services and Prices, 2013. Tampere, Finland: Tampere University Hospital; 2013.
      • 15.
        Soini E, Hallinen T. Cost-utility of agomelatine, venlafaxine and placebo in the treatment of major depressive disorder (MDD) in Finland – Economic modelling study using representative population data. Value Health. 2009;12:A359.
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        NHS Choices. Diarrhoea: NHS; 2013.
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        van Hoek AJ, Underwood A, Jit M, Miller E, Edmunds WJ. The impact of pandemic influenza H1N1 on health-related quality of life: a prospective population-based study. PloS one. 2011;6:e17030.

      Supplement C. Probabilistic Sensitivity Analysis Results

      Probabilistic Results

      Table C.I reports the 15-year mean and 2.5%–97.5% percentile results based on 2000 simulations.
      Table C.IProbabilistic results.
      TreatmentMean QALYs2.5%97.5%Mean costs (€)2.5%97.5%
      DMF7.3356.8477.781376,159335,827420,955
      Teriflunomide7.2426.7417.683369,045327,547415,265
      IFNβ-1a-SC 44µg7.1126.6127.556373,417329,267419,587
      GA6.9906.4457.457393,558352,185440,894
      IFNβ-1a-IM 30µg6.9716.4157.444387,785344,135436,228
      IFNβ-1b-SC 250µg6.5756.0037.095428,286380,681482,486
      DMF = dimethyl fumarate; GA = glatiramer acetate; IFNβ-1a-SC = interferon beta-1a-subcutaneous; IFNβ-1a-IM = interferon beta-1a-intramuscular; IFNβ-1b-SC = interferon beta-1b-subcutaneous; QALY = quality-adjusted life-year.

      Cost-Effectiveness Plane

      Figure C.1 shows the joint distributions of 15-year cost-and-effect differences (increments) for the nondominated teriflunomide (teriflunomide is in the origin of Figure C.1) vs other DMTs.
      Figure C.1.
      Figure C.1Probabilistic incremental cost and QALY results in a cost-effectiveness plane for teriflunomide vs other first-line treatments (2000 simulations). DMF = dimethyl fumarate; GA = glatiramer acetate; IFNβ-1a-SC = interferon beta-1a-subcutaneous; IFNβ-1a-IM = interferon beta-1a-intramuscular; IFNβ-1b-SC = interferon beta-1b-subcutaneous; QALY = quality-adjusted life-year.

      Cost-Effectiveness Acceptability Frontier

      Figure C.2 depicts the cost-effectiveness acceptability frontier (CEAF). Based on the CEAF, teriflunomide had more than 50% cost-effectiveness probabilities with ICERs less than 77,416 vs other first-line DMTs for RRMS (Figure C.2).
      Figure C.2.
      Figure C.2Cost-effectiveness acceptability frontier for first-line treatments. DMF = dimethyl fumarate; QALY = quality-adjusted life-year.

      Bayesian Treatment Ranking

      According to Bayesian treatment ranking, teriflunomide was the best option, with a willingness-to-pay threshold of €0 (99.9%), €25,000 (100.0%), €37,000 (100.0%), €55,000 (96.2%), and €68,000 (75.2%) per QALY gained.

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        The epidemiology of multiple sclerosis in Europe.
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        Atlas multiple sclerosis resources in the world 2008.
        World Health Organization, Geneva, Switzerland2008: 1-56
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        • Murtonen A.
        • Elovaara I.
        • Sumelahti M.L.
        Increased female MS incidence and differences in gender-specific risk in medium- and high-risk regions in Finland from 1981-2010.
        Multiple Sclerosis International. 2013; 2013: 182516
        • Sumelahti M.L.
        • Tienari P.J.
        • Hakama M.
        • Wikstrom J.
        Multiple sclerosis in Finland: incidence trends and differences in relapsing remitting and primary progressive disease courses.
        J Neurol Neurosurg Psychiatry. 2003; 74: 25-28
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        • Tienari P.J.
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        Regional and temporal variation in the incidence of multiple sclerosis in Finland 1979-1993.
        Neuroepidemiology. 2000; 19: 67-75
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        Increasing prevalence of multiple sclerosis in Finland.
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