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Cost-Effectiveness Analysis of Etanercept 25 mg Maintenance Therapy After Treatment with Etanercept 50 mg for Moderate Rheumatoid Arthritis in the PRESERVE Trial in Japan

Open AccessPublished:December 16, 2021DOI:https://doi.org/10.1016/j.vhri.2021.06.012

      Highlights:

      • Once patients with rheumatoid arthritis have achieved remission or low disease activity, physicians sometimes choose to decrease the dose of the tumor necrosis factor inhibitor. There are several reasons for this; one of which is cost. However, data on the cost-effectiveness of reducing the dose are limited.
      • We conducted Markov modeling to estimate the cost-effectiveness of a maintenance dose of etanercept 25 mg/week plus methotrexate (MTX) in patients with rheumatoid arthritis in Japan who had achieved remission or low disease activity on etanercept 50 mg/week plus MTX. Our analysis utilized etanercept 25 mg/week treatment data from a randomized, controlled clinical trial. All parameters (clinical, utility, and cost) were based on published data and information from government agencies.
      • We calculated an incremental cost-effectiveness ratio of ¥6 173 772, and then evaluated the incremental cost-effectiveness ratio according to published guidelines for determining cost-effectiveness, including those from the World Health Organization. The results suggest that maintenance therapy with etanercept 25 mg/week plus MTX in Japan is cost-effective.

      Abstract

      Objectives

      To use Markov modeling to estimate the cost-effectiveness of treatment with etanercept 25 mg once weekly plus methotrexate (MTX) in Japanese patients with rheumatoid arthritis who had achieved remission or low disease activity with etanercept 50 mg once weekly plus MTX.

      Methods

      Effectiveness data were estimated based on results from a clinical trial (PRESERVE) in patients with rheumatoid arthritis who had achieved remission or low disease activity and who were then randomized to receive etanercept 25 mg plus MTX or placebo plus MTX. A Markov model was established and included flare rates of 21% and 62% in the etanercept 25 mg and placebo groups, respectively. EQ-5D was calculated using an ordinary least-squares model that included the health assessment questionnaire disability index and pain visual analog scale. Worsening of the health assessment questionnaire score over 1 year was estimated to be 0.047 for patients with flare, and when associated with radiographic progression it was estimated to increase by 0.006 and 0.025 in the etanercept 25 mg and placebo groups, respectively. A cycle length of 1 year was applied to calculate the cumulative cost and effectiveness for a 10-year time span.

      Results

      Compared with the placebo group, the quality-adjusted life-years for the etanercept 25 mg group was increased by 0.841. The incremental cost-effectiveness ratio was ¥6 173 772.

      Conclusion

      These results suggest that maintenance treatment with etanercept 25 mg is cost-effective.

      Keywords

      Introduction

      Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint pain and stiffness that may progress to joint destruction and disability.
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      The prevalence of RA in Japan is estimated to be between 0.6% and 1.0%,
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      which is comparable with the prevalence in other parts of the world.
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      Thus, the socioeconomic impact of RA in Japan cannot be disregarded.
      Targeted therapies such as biological disease-modifying antirheumatic drugs (bDMARDs) are effective in inhibiting the progression of structural damage and improving physical function in patients with RA and moderate to high disease activity.
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      Five tumor necrosis factor (TNF) inhibitors are available in Japan: etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab.
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      The interleukin-6 inhibitors, tocilizumab and sarilumab, as well as the cluster of differentiation (CD)-80/CD86 inhibitor, abatacept, are also available in Japan for the treatment of RA.
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      [email protected]: FDA approved drug products.
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      List of approved products.
      In the few head-to-head randomized clinical trials that have assessed the comparative effectiveness of biologics in the treatment of RA, comparable efficacy has generally been demonstrated.
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      RA requires long-term treatment, and this can result in a high economic burden for patients, payers, and society.
      • Fautrel B.
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      In Japan, the annual drug cost of etanercept 50 mg/week is approximately ¥1.6 million.
      Ministry of Health, Labour and Welfare
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      ,
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      The cost of treating RA varies widely across countries,
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      partly because of the varied use of bDMARDs, which are substantially more expensive than conventional synthetic DMARDs (csDMARDs).
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      Economic benefits of optimizing anchor therapy for rheumatoid arthritis.
      ,
      • Schoels M.
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      • et al.
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      ,
      • Spalding J.R.
      • Hay J.
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      The use of biologics for the treatment of RA has caused concern with regard to the impact of drug costs on direct medical expenses; data from 1 published study have shown, however, that the improvement in functional status and the reduction in healthcare resource use resulting from the use of biologic therapy largely offsets the increased drug costs.
      • Huscher D.
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      • von Hinüber U.
      • et al.
      Evolution of cost structures in rheumatoid arthritis over the past decade.
      Once patients have achieved remission or low disease activity (LDA), physicians may decide to decrease the dose of the biologic for several reasons, including concerns about infection or adverse events, or to decrease costs.
      • Schett G.
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      • Tanaka Y.
      • et al.
      Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions.
      According to systematic literature reviews, decreasing the dose of the biologic is an acceptable option for certain patients.
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      • Jacobs J.W.G.
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      • Luime J.J.
      Flare rate in patients with rheumatoid arthritis in low disease activity or remission when tapering or stopping synthetic or biologic DMARD: a systematic review.
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      Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.
      • Edwards C.J.
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      Dosing down with biologic therapies: a systematic review and clinicians’ perspective.
      • Lau C.S.
      • Gibofsky A.
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      • et al.
      Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review.
      Maintenance of remission or LDA following dose reduction of etanercept has been evaluated in several studies
      • Emery P.
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      • FitzGerald O.
      • et al.
      Sustained remission with etanercept tapering in early rheumatoid arthritis.
      • Smolen J.S.
      • Nash P.
      • Durez P.
      • et al.
      Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial.
      • van Vollenhoven R.F.
      • Østergaard M.
      • Leirisalo-Repo M.
      • et al.
      Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis.
      ; data on the cost-effectiveness of reducing the dose are, however, limited,
      • Kobelt G.
      Treating to target with etanercept in rheumatoid arthritis: cost-effectiveness of dose reductions when remission is achieved.
      and we are not aware of such data for Japan. In Japan, etanercept is the only bDMARD approved for RA for which the higher dose (50 mg/week) is the standard dose rather than the lower dose (25 mg/week).
      Pharmaceuticals and Medical Devices Agency
      List of approved products.
      Therefore, it is of interest to analyze the cost-effectiveness of decreasing the dose of etanercept in Japan.
      In this analysis, we used data from a randomized controlled clinical trial to conduct Markov modeling to estimate the cost-effectiveness of a maintenance dose of etanercept 25 mg/week plus methotrexate (MTX) in patients with RA in Japan who had achieved remission or LDA on etanercept 50 mg/week plus MTX.

      Methods

       Study design

      A Markov model was developed to perform a cost-effectiveness analysis of etanercept 25 mg/week maintenance therapy after treatment with etanercept 50 mg/week and MTX in patients with moderate RA (see Appendix Figure 1 in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2021.06.012). Analysis cycles of 1 year and 10 years were used for the base-case analysis to evaluate long-term progression of RA. The discount rate for both cost and effectiveness was defined as 2%,
      • Shiroiwa T.
      • Fukuda T.
      • Ikeda S.
      • Takura T.
      • Moriwaki K.
      Development of an official guideline for the economic evaluation of drugs/medical devices in Japan.
      and the outcome measure was quality-adjusted life-years (QALYs). Analyses were performed assuming the use of public health insurance, and only direct health costs were included in the calculations.

       Patients

      This analysis included data from the randomized controlled clinical trial, PRESERVE.
      • Smolen J.S.
      • Nash P.
      • Durez P.
      • et al.
      Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial.
      PRESERVE was a global trial but it was not conducted in Japan. In PRESERVE, patients with RA and moderate disease activity who had achieved sustained LDA on etanercept 50 mg/week plus MTX in period 1 (mean disease activity score in 28 joints [DAS28] ≤3.2 from weeks 12 to 36 and DAS28 ≤3.2 at week 36) were randomized to 1 of 3 treatment arms in period 2: (1) etanercept 50 mg/week plus MTX, (2) etanercept 25 mg/week plus MTX, or (3) placebo plus MTX.
      • Smolen J.S.
      • Nash P.
      • Durez P.
      • et al.
      Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial.
      In this analysis, we compared the etanercept 25 mg/week plus MTX group to the placebo plus MTX group. A schematic illustration of the model is provided in Appendix Figure 1 in Supplemental Materials found at https://doi.org/10.1016/j.vhri.2021.06.012. Patient-reported outcome (PRO) data were taken from an analysis conducted by Smolen et al
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      ,

      Smolen JS, Jones H, Mahgoub E, Pedersen R, Marshall L. Association between flare and radiographic progression in patients with rheumatoid arthritis. Poster presented at: 2016 Annual Meeting of the American College of Rheumatology, November 2011-2016, Washington, DC.

      that evaluated PROs during period 2 of PRESERVE in patients with flare (DAS28 >5.1 or DAS28 >3.2 at 2 or more time points) and without flare (DAS28 ≤3.2).

       Variables

       Clinical parameters

      The flare rates used in this analysis were taken from Smolen et al
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      ,

      Smolen JS, Jones H, Mahgoub E, Pedersen R, Marshall L. Association between flare and radiographic progression in patients with rheumatoid arthritis. Poster presented at: 2016 Annual Meeting of the American College of Rheumatology, November 2011-2016, Washington, DC.

      and were 21% and 62% in the etanercept 25 mg and placebo groups, respectively (P<.001).

       Utility parameters

      Utility parameters were estimated based on the pain visual analog scale (VAS) and the health assessment questionnaire (HAQ) score from Smolen et al
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      ,

      Smolen JS, Jones H, Mahgoub E, Pedersen R, Marshall L. Association between flare and radiographic progression in patients with rheumatoid arthritis. Poster presented at: 2016 Annual Meeting of the American College of Rheumatology, November 2011-2016, Washington, DC.

      and from a mapping study of the EQ-5D-3L.
      • Kim H.-L.
      • Kim D.
      • Jang E.J.
      • et al.
      Mapping health assessment questionnaire disability index (HAQ-DI) score, pain visual analog scale (VAS), and disease activity score in 28 joints (DAS28) onto the EuroQol-5D (EQ-5D) utility score with the Korean Observational study Network for Arthritis (KORONA) registry data.
      That study investigated the mapping algorithm for the utility value of the EQ-5D-3L from the HAQ disability index (HAQ-DI), the DAS28 using C-reactive protein (DAS28-CRP), and the pain VAS value using a dataset of 2846 patients with RA in Korea.
      • Kim H.-L.
      • Kim D.
      • Jang E.J.
      • et al.
      Mapping health assessment questionnaire disability index (HAQ-DI) score, pain visual analog scale (VAS), and disease activity score in 28 joints (DAS28) onto the EuroQol-5D (EQ-5D) utility score with the Korean Observational study Network for Arthritis (KORONA) registry data.
      Because the referenced study reported the DAS28 score based on the erythrocyte sedimentation rate rather than CRP,
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      the following ordinary least-squares model was used in the analysis:
      EQ5D=0.930.22(HAQDI)0.26(Pain VAS)


      The change in HAQ scores in period 2 of the PRESERVE study was categorized based on the results of a study by Nikiphorou et al
      • Nikiphorou E.
      • Norton S.
      • Young A.
      • et al.
      Association between rheumatoid arthritis disease activity, progression of functional limitation and long-term risk of orthopaedic surgery: combined analysis of two prospective cohorts supports EULAR treat to target DAS thresholds.
      that evaluated long-term progression of RA. In that study, HAQ progression was stratified according to disease activity category (eg, remission: DAS28 ≤2.6, LDA: DAS28 >2.6-3.2, low-moderate: DAS28 ≥3.2-4.19, high-moderate: DAS28 ≥4.2-5.1, and high: DAS28 >5.1).
      • Nikiphorou E.
      • Norton S.
      • Young A.
      • et al.
      Association between rheumatoid arthritis disease activity, progression of functional limitation and long-term risk of orthopaedic surgery: combined analysis of two prospective cohorts supports EULAR treat to target DAS thresholds.
      The mean DAS28 at the beginning of period 2 in PRESERVE in the patients with flare was 2.3 and the change in DAS28 in these patients was 1.4
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      ; thus, we calculated the mean DAS28 score at the end of period 2 to be 3.7 for patients with flare. In the study by Nikiphorou et al,
      • Nikiphorou E.
      • Norton S.
      • Young A.
      • et al.
      Association between rheumatoid arthritis disease activity, progression of functional limitation and long-term risk of orthopaedic surgery: combined analysis of two prospective cohorts supports EULAR treat to target DAS thresholds.
      this value was categorized as low-moderate disease activity and the annual progression in HAQ scores for patients with this level of disease activity was 0.047. Therefore, we estimated the annual progression of the HAQ score to be 0.047 among patients with continuous flare. Table 1 shows the flare rate and quality-of-life parameters considered in this analysis.
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      ,

      Smolen JS, Jones H, Mahgoub E, Pedersen R, Marshall L. Association between flare and radiographic progression in patients with rheumatoid arthritis. Poster presented at: 2016 Annual Meeting of the American College of Rheumatology, November 2011-2016, Washington, DC.

      As an example, a utility value for the patients with flare 2 years after baseline was estimated using the following calculation:
      0.607=0.930.22(0.51+0.44+0.047×2 years)0.26(16.4+19.4)/100


      Table 1Flare rate and quality-of-life parameters.
      ParameterValue
      Flare rate
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      ,

      Smolen JS, Jones H, Mahgoub E, Pedersen R, Marshall L. Association between flare and radiographic progression in patients with rheumatoid arthritis. Poster presented at: 2016 Annual Meeting of the American College of Rheumatology, November 2011-2016, Washington, DC.

       Placebo group
      Both study groups also included methotrexate.
      62%
       Etanercept 25 mg/week group
      Both study groups also included methotrexate.
      21%
      QoL (baseline value + amount of change)

      Smolen JS, Jones H, Mahgoub E, Pedersen R, Marshall L. Association between flare and radiographic progression in patients with rheumatoid arthritis. Poster presented at: 2016 Annual Meeting of the American College of Rheumatology, November 2011-2016, Washington, DC.

       Patients with flare, overall study population
      HAQ-DI0.51 + 0.44
      Pain VAS16.4 + 19.4
       Patients without flare, overall study population
      HAQ-DI0.44 + 0.01
      Pain VAS11.8 + 2.8
      HAQ-DI indicates health assessment questionnaire disability index; QoL, quality of life; VAS, visual analog scale.
      Both study groups also included methotrexate.
      Over 1 year, the worsening in the HAQ score associated with radiographic progression has been estimated to be 0.025 in patients with RA who are taking csDMARDs, including MTX, and 0.006 in patients who are taking a TNF inhibitor plus MTX.
      • Smolen J.S.
      • Aletaha D.
      • Grisar J.C.
      • Stamm T.A.
      • Sharp J.T.
      Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials.
      We calculated the difference between these treatment regimens (0.019) and added an additional annual increase in HAQ score of 0.019 to the placebo group compared with the etanercept 25 mg group.

       Cost parameters

      The cost parameters considered in this analysis (Table 2) are from the National Health Insurance Medical Treatment Fees and Drug Prices, which are the latest sources of cost data for the analysis.
      Ministry of Health, Labour and Welfare
      List of drugs and generics by 30 Sep 2019 [Japanese].
      ,
      Ministry of Health, Labour and Welfare
      Medical Treatment Fee Revision [Japanese].
      The frequency of outpatient visits was assumed to be once a month for the etanercept 25 mg and placebo groups. A management fee for self-injection at home was taken into account whenever etanercept was administered.
      Table 2Cost parameters
      ItemsCost (¥/month)
      Placebo group(Maintenance treatment)Etanercept 25 mg/wk group(Maintenance treatment)Etanercept 50 mg/wk group(Induction treatment)
      A001 Outpatient visit720720720
      A001 Outpatient management premium520520520
      F400 Prescription fee (Others)680680680
      C101 At home self-injection guidance andmanagement fee065006500
      D005 Blood count test210210210
      D026 Physician’s fee for blood count test125012501250
      D007 Biochemical test (more than 10 items)115011501150
      D026 Physician’s fee for biochemical test144014401440
      D015 CRP160160160
      D026 Physician’s fee for CRP144014401440
      Drug cost015 944 × 431 069 × 4
      Total757077 846138 346
      From the National Health Insurance Medical Treatment Fees and Drug Prices.
      Ministry of Health, Labour and Welfare
      List of drugs and generics by 30 Sep 2019 [Japanese].
      ,
      Ministry of Health, Labour and Welfare
      Medical Treatment Fee Revision [Japanese].
      CRP indicates C-reactive protein.
      For the cost of flare episodes, patients in the flare group were assumed to experience 2 flares per year (the length of period 2 in the PRESERVE study), for which they were treated with etanercept 50 mg/week for 3 months and then achieved remission or LDA again.

       Data Sources and Data Management

      All parameters (clinical, utility, and cost) used in the analysis were based on published data and information from government agencies. The TreeAge Pro 2019 software package (TreeAge Software Inc., Williamstown, MA) was used to develop the analysis model.

       Data analysis

      A cycle length of 1 year was applied to calculate the cumulative cost and effectiveness throughout a 10-year time span. Following the Japanese guidelines for cost-effectiveness analysis, the analysis was conducted from the perspective of the healthcare payer.
      • Shiroiwa T.
      • Fukuda T.
      • Ikeda S.
      • Takura T.
      • Moriwaki K.
      Development of an official guideline for the economic evaluation of drugs/medical devices in Japan.
      QALYs were used as an effectiveness measure, and only direct medical costs incurred for treatment were considered in the analysis.
      • Shiroiwa T.
      • Fukuda T.
      • Ikeda S.
      • Takura T.
      • Moriwaki K.
      Development of an official guideline for the economic evaluation of drugs/medical devices in Japan.
      An annual discount rate of 2% was adopted for future costs and effectiveness to evaluate the results as current values.
      • Shiroiwa T.
      • Fukuda T.
      • Ikeda S.
      • Takura T.
      • Moriwaki K.
      Development of an official guideline for the economic evaluation of drugs/medical devices in Japan.
      A 1-way sensitivity analysis was performed to evaluate the impact of each parameter on the result. The range for each parameter in the sensitivity analysis was the 95% confidence interval (95% CI); nonetheless, we used ±20% of the base-case values of the cost parameters. These were calculated using the fixed official medical fee and drug cost in Japan. In addition, a probabilistic sensitivity analysis was performed with 10 000 Monte Carlo simulations to evaluate the uncertainty of the results. Stochastic parameters and utility parameters were assumed to have a beta distribution, normal distribution of coefficient data in the mapping algorithm was assumed, and cost parameters were assumed to have a gamma distribution.

      Results

       Base-case Cost-effectiveness Analysis

      The expected QALYs were 6.770 for etanercept 25 mg and 5.929 for placebo; an increase of 0.841 QALYs was expected for etanercept 25 mg (Table 3). Total medical costs were ¥10 471 283 for etanercept 25 mg and ¥5 278 091 for placebo. Thus, the incremental cost-effectiveness ratio (ICER) for etanercept 25 mg was ¥6 173 772.
      Table 3Results of base-case cost-effectiveness analysis.
      ParameterPlacebo groupEtanercept25 mg/week groupDifference
      Cost (¥)5 278 09110 471 2835 193 191
      QALY5.9296.7700.841
      ICER (¥/QALY)6 173 772
      ICER indicates incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

       Sensitivity Analysis

      Figure 1 shows the results of the 1-way sensitivity analysis, and Figures 2 and 3 show the results of the probabilistic sensitivity analysis. The variables that primarily influenced the analysis are the flare rates in the 1-way sensitivity analysis. Assuming an ICER threshold of ¥10 million, the probability that the ICER was below the threshold was 97.8% for etanercept 25 mg (the probabilities of cost-effectiveness were 19.8%, 80.0%, and 99.9% with thresholds of ¥5 million, ¥7.5 million, and ¥15 million, respectively).
      Figure thumbnail gr1
      Figure 1Results of 1-way sensitivity analysis. The base-case value is shown as the central vertical line. The red bar represents the result when the parameter was changed to a high value (ie, the parameter changed to +20%), and the blue bar represents the result when it was changed to a low value (−20%).
      ETN indicates etanercept; HAQ-DI, health assessment questionnaire disability index; QALY, quality-adjusted life-year; VAS, visual analog scale; WTP, willingness-to-pay.
      Figure thumbnail gr2
      Figure 2Scatter plot of probabilistic sensitivity analysis. The lines indicate the reference value of ICER. The probability of being cost-effective (eg, ICER <¥5 million) can be evaluated by counting the number of plots that are located below the reference line.
      ICER indicates incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
      Figure thumbnail gr3
      Figure 3Cost-effectiveness acceptability curve. The curved line shows the relationship between the probability of being cost-effective and the willingness to pay per 1 QALY gained.
      QALY indicates quality-adjusted life-year.

      Discussion

      In general, a treatment is considered to be cost-effective if the ICER is lower than the prespecified threshold for the analysis
      • Owens D.K.
      Interpretation of cost-effectiveness analyses.
      ; however, no clear threshold for ICER has been defined in Japan. In other countries, there are fixed criteria for cost-effectiveness, eg, the National Institute for Health and Care Excellence lists the threshold for ICER in the range of £20 000/QALY to £30 000/QALY (from ¥3 000 000/QALY to ¥4 500 000/QALY at the exchange rate of ¥150 to £1
      Reiwa 2nd year medical fee points Medical department [Japanese].
      ) in its guideline for cost-effectiveness analyses.

      National Institute for Health and Care Excellence. Guide to the methods of technology Appraisal 2013, process and methods. https://www.nice.org.uk/process/pmg9/chapter/the-appraisal-of-the-evidence-and-structured-decision-making. Accessed May 29, 2019

      Laupacis et al
      • Laupacis A.
      • Feeny D.
      • Detsky A.S.
      • Tugwell P.X.
      How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations.
      list the threshold as $20 000/QALY to $100 000/QALY (from ¥2 200 000 to ¥11 000 000 at the exchange rate of ¥110 to $1).
      Reiwa 2nd year medical fee points Medical department [Japanese].
      If the upper limit of these reference values is used, then the ICER of ¥6 173 772 is considered cost-effective.
      Additionally, the World Health Organization has stated that one method of determining a cost-effectiveness threshold is to base it on a country’s per capita gross domestic product (GDP).
      • Bertram M.
      • Lauer J.
      • De Joncheere K.
      • et al.
      Cost–effectiveness thresholds: pros and cons.
      Specifically, a treatment that costs less than 3 times the GDP is considered cost-effective.
      • Bertram M.
      • Lauer J.
      • De Joncheere K.
      • et al.
      Cost–effectiveness thresholds: pros and cons.
      The per capita GDP in Japan is ¥4 321 000
      • Verhoef L.M.
      • Bos D.
      • van den Ende C.
      • et al.
      Cost-effectiveness of five different anti-tumour necrosis factor tapering strategies in rheumatoid arthritis: a modelling study.
      ; if the per capita GDP is tripled to ¥12 963 000, then the ICER of ¥6 173 772 is considered cost-effective.
      Surveys conducted in Japan found the willingness to pay (WTP) for 1 QALY to be approximately ¥6 700 000 and ¥5 000 000, as reported by Ohkusa et al
      • Ohkusa Y.
      • Sugawara T.
      Research for willingness to pay for one QALY gain.
      and Shiroiwa et al
      • Shiroiwa T.
      • Sung Y.-K.
      • Fukuda T.
      • Lang H.C.
      • Bae S.C.
      • Tsutani K.
      International survey on willingness-to-pay (WTP) for one additional QALY gained: what is the threshold of cost effectiveness?.
      , respectively. Tanno et al
      • Tanno M.
      • Nakamura I.
      • Ito K.
      • et al.
      Modeling and cost-effectiveness analysis of etanercept in adults with rheumatoid arthritis in Japan: a preliminary analysis.
      conducted Markov modeling to calculate the ICER of etanercept 25 mg compared with csDMARDs in Japanese patients with RA in which treatment with bucillamine failed. They calculated the ICER to be ¥2 500 000/QALY.
      • Tanno M.
      • Nakamura I.
      • Ito K.
      • et al.
      Modeling and cost-effectiveness analysis of etanercept in adults with rheumatoid arthritis in Japan: a preliminary analysis.
      Importantly, our analysis evaluated the cost-effectiveness of etanercept 25 mg in patients who had already achieved treat-to-target. We are not aware of any other studies that have conducted such an analysis in Japan. Interestingly, the ICER that we calculated falls between the WTP survey results from Ohkusa et al and Shiroiwa et al.
      • Ohkusa Y.
      • Sugawara T.
      Research for willingness to pay for one QALY gain.
      ,
      • Shiroiwa T.
      • Sung Y.-K.
      • Fukuda T.
      • Lang H.C.
      • Bae S.C.
      • Tsutani K.
      International survey on willingness-to-pay (WTP) for one additional QALY gained: what is the threshold of cost effectiveness?.
      Although the PRESERVE study was not conducted in Japan, we have applied the results to Japanese health economics. Our approach took into consideration that there are only minor discrepancies in the prevalence and severity of RA (particularly among patients receiving bDMARDs) between the European/US and Japanese populations.
      • Yamanaka H.
      • Sugiyama N.
      • Inoue E.
      • Taniguchi A.
      • Momohara S.
      Estimates of the prevalence of and current treatment practices for rheumatoid arthritis in Japan using reimbursement data from health insurance societies and the IORRA cohort (I).
      ,
      • Scott D.L.
      • Wolfe F.
      • Huizinga T.W.J.
      Rheumatoid arthritis.
      Markov modeling was also conducted by Kobelt to evaluate the cost-effectiveness of etanercept 25 mg/week in Sweden, using data from the PRESERVE trial and from a registry in Sweden to extrapolate the results to 10 years.
      • Kobelt G.
      Treating to target with etanercept in rheumatoid arthritis: cost-effectiveness of dose reductions when remission is achieved.
      Unlike the current analysis, that study compared the cost-effectiveness of continuing etanercept 50 mg/week, decreasing the dose to 25 mg/week, or discontinuing etanercept. The analysis found that the 25 mg/week dose of etanercept was advantageous over the 50 mg/week dose, based on the cost/QALY gained. The model predicted a higher cost/QALY over time due to increases in the cost of etanercept; nonetheless, the 25 mg/week dose was still the preferred option. Another Markov modeling study was performed by Verhoef et al
      • Verhoef L.M.
      • Bos D.
      • van den Ende C.
      • et al.
      Cost-effectiveness of five different anti-tumour necrosis factor tapering strategies in rheumatoid arthritis: a modelling study.
      in The Netherlands to evaluate the cost-effectiveness of tapering TNF inhibitors. The authors used data from the Dose Reduction Strategy of Subcutaneous TNF inhibitors clinical trial
      • van Herwaarden N.
      • van der Maas A.
      • Minten M.J.
      • et al.
      Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial.
      and the Spacing of TNF-blocker injections in Rheumatoid Arthritis Study,
      • Fautrel B.
      • Pham T.
      • Alfaiate T.
      • et al.
      Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: spacing of TNF-blocker injections in rheumatoid arthritis Study).
      as well as the Nijmegen RA cohort
      • Welsing P.M.
      • van Riel P.L.
      The Nijmegen inception cohort of early rheumatoid arthritis.
      to model several dose-tapering regimens for etanercept and adalimumab over 18 months. The authors found that a 4- or 5-step tapering strategy was more cost-effective than continuing treatment at the full dose; nonetheless, patients did experience more short-lived flares.
      • Verhoef L.M.
      • Bos D.
      • van den Ende C.
      • et al.
      Cost-effectiveness of five different anti-tumour necrosis factor tapering strategies in rheumatoid arthritis: a modelling study.
      This analysis has several limitations. First, we made the assumption that the patients who flared were treated with etanercept 50 mg/week plus MTX. Because this information was not provided,
      • Smolen J.S.
      • Pedersen R.
      • Jones H.
      • Mahgoub E.
      • Marshall L.
      Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.
      long-term prognoses were estimated using information from the literature.
      • Nikiphorou E.
      • Norton S.
      • Young A.
      • et al.
      Association between rheumatoid arthritis disease activity, progression of functional limitation and long-term risk of orthopaedic surgery: combined analysis of two prospective cohorts supports EULAR treat to target DAS thresholds.
      ,
      • Smolen J.S.
      • Aletaha D.
      • Grisar J.C.
      • Stamm T.A.
      • Sharp J.T.
      Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials.
      It has been reported that although intermittent treatment of flares has clinical efficacy,
      • Inui K.
      • Koike T.
      • Tada M.
      • et al.
      Clinical and radiologic analysis of on-demand use of etanercept for disease flares in patients with rheumatoid arthritis for 2 years: the RESUME study: A case-control study.
      fluctuation of disease activity is associated with radiographic progression.
      • Inui K.
      • Koike T.
      • Tada M.
      • et al.
      Clinical and radiologic analysis of on-demand use of etanercept for disease flares in patients with rheumatoid arthritis for 2 years: the RESUME study: A case-control study.
      ,
      • Welsing P.M.J.
      • Landewé R.B.M.
      • Van Riel P.L.C.M.
      • et al.
      The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: A longitudinal analysis.
      In clinical practice, the frequency of medical visits in patients with flare may be higher than in patients without flare, and we did not account for this difference. In addition, it is possible that the results for the MTX plus placebo group may be an overestimation of the effectiveness of MTX alone, due to the placebo effect.
      Another limitation is that the costs of medical visits should be included and should be based on real-world data. Radner et al
      • Radner H.
      • Smolen J.S.
      • Aletaha D.
      Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs.
      reported that in patients with RA, indirect costs increase with an increase in the HAQ score. The authors assigned indirect costs to 3 categories of HAQ scores, and the lowest score catergory was HAQ ≤1.2.
      • Radner H.
      • Smolen J.S.
      • Aletaha D.
      Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs.
      Because the mean HAQ scores in our study only ranged from 0.4 to 0.5 for all patients,

      Smolen JS, Jones H, Mahgoub E, Pedersen R, Marshall L. Association between flare and radiographic progression in patients with rheumatoid arthritis. Poster presented at: 2016 Annual Meeting of the American College of Rheumatology, November 2011-2016, Washington, DC.

      the data from Radner et al
      • Radner H.
      • Smolen J.S.
      • Aletaha D.
      Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs.
      were not meaningful in our analysis. Lastly, a new, more up to date WTP analysis may be required to determine the threshold that is currently appropriate.

      Conclusion

      Maintenance therapy with etanercept 25 mg/week plus MTX appears to be cost-effective if the upper limit of the reference value is $100 000 or if the World Health Organization’s standard cost-effective value of triple the per capita GDP is applied as the threshold.

      Article and Author Information

      Author Contributions: Concept and design: Hirose, Kawaguchi, Murata
      Acquisition of data: Hirose, Murata
      Analysis and interpretation of data: Hirose, Kawaguchi, Murata, Atsumi
      Drafting of the manuscript: Hirose, Murata
      Critical revision of the paper for important intellectual content: Hirose, Kawaguchi, Murata, Atsumi
      Statistical analysis: Murata
      Administrative, technical, or logistic support: Murata
      Supervision: Atsumi
      Conflict of Interest Disclosures: Dr Hirose is an employee and stockholder in Pfizer Japan Inc; and reported receiving personal fees from Pfizer Japan Inc. Dr Kawaguchi is an employee of Pfizer; and reported receiving funding from Pfizer outside the submitted work. Dr Murata reported receiving funding from Pfizer during the conduct of this study. Dr Atsumi reported receiving grants or contracts from Astellas Pharma Inc, Takeda Pharmaceutical Co Ltd, Mitsubishi Tanabe Pharma Co, Chugai Pharmaceutical Co Ltd, Daiichi Sankyo Co Ltd, Otsuka Pharmaceutical Co, Pfizer Inc, Alexion Inc, Teijin Pharma Limited, Novartis Pharma K.K., Eli Lilly Japan K.K., Kyowa Kirin Co Ltd, and Taiho Pharmaceutical Co Ltd, outside the submitted work; consulting fees from AstraZeneca plc, Medical & Biological Laboratories Co Ltd, Ono Pharmaceutical Co Ltd, AbbVie Inc, Pfizer Inc, Novartis Pharma K.K., Nippon Boehringer lngelheim Co Ltd, Pfizer Inc, and Mitsubishi Tanabe Pharma Co outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc, Takeda Pharmaceutical Co Ltd, Pfizer Inc, AbbVie Inc, Eisai Co Ltd, Daiichi Sankyo Co Ltd, Bristol-Myers Squibb Co, UCB Japan Co Ltd, and Eli Lilly Japan K.K. outside the submitted work.
      Funding/Support: This study was sponsored by Pfizer .
      Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

      Acknowledgment

      Medical writing support was provided by Jennica Lewis, PharmD, CMPP of Engage Scientific Solutions and was funded by Pfizer .
      Data Availability: Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

      Supplemental Material

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