Persistence, adherence, healthcare resource utilisation and costs for interferon Beta in multiple sclerosis: a population-based study in the Campania region (southern Italy).

BACKGROUND: To differentiate five formulations of Interferon Beta for the treatment of multiple sclerosis (MS) in clinical practice, by analysing persistence, adherence, healthcare resource utilisation and costs at population level. METHODS: In this population-based study, we included individuals with MS living in the Campania Region of Italy from 2015 to 2017, on treatment with intramuscular Interferon Beta-1a (Avonex® = 618), subcutaneous pegylated Interferon Beta-1a (Plegridy® = 259), subcutaneous Interferon Beta-1a (Rebif® = 1220), and subcutaneous Interferon Beta-1b (Betaferon® = 348; and Extavia® = 69). We recorded healthcare resource utilisation from administrative databases (hospital discharges, drug prescriptions, MS-related outpatients), and derived costs from the Regional formulary. We classified hospital admissions into MS-related and non-MS-related. Persistence (time to switch to other disease modifying treatments (DMTs)), and adherence (medication possession ratio (MPR) = medication supply obtained/medication supply expected during follow-up period) were calculated. RESULTS: Patients treated with Rebif® were younger, when compared with other Interferon Beta formulations (p < 0.01). The probability of switching to other DMTs was 60% higher for Betaferon®, 90% higher for Extavia®, and 110% higher for Plegridy®, when compared with Rebif® (p < 0.01). Plegridy® presented with 7% higher adherence (p < 0.01), and Betaferon® with 3% lower adherence (p = 0.03), when compared with Rebif®. The probability of MS-related hospital admissions was 40% higher in Avonex® (p = 0.03), 400% higher in Betaferon® (p < 0.01), and 60% higher in Plegridy® (p = 0.04), resulting into higher non-DMT-related costs, when compared with Rebif®. DISCUSSION: Interferon Beta formulations presented with different prescription patterns, persistence, adherence, healthcare resource utilisation and costs, with Rebif® being used in younger patients and with less MS-related hospital admissions.

A new approach to pharmaceutical pricing based on patients' willingness to pay.

OBJECTIVES: Pharmaceutical pricing is an important and contentious issue in middle- and low-income countries. The present study evaluated a value-based pricing system for estimating the price of interferon-beta (IFN-ß). METHODS: Prices were estimated through the Willingness to Pay (WTP) system using the Discrete Choice Experiment (DCE) from the viewpoint of MS patients, levels of attributes and patients' willingness to pay for these attributes. RESULTS: The results indicate that the new approach to pricing medicines leads to more integrated prices than the current system. The current prices of four brands were higher than their pharmaceutical market price; the prices of other brands were consistent with it. CONCLUSION: Application of the proposed pricing system will help pharmaceutical companies make realistic price estimates of their products while accounting for patient preferences, which may enhance patients' adherence to treatment.

Routine interferon-neutralising antibody testing in patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis is a leading cause of disability in young adults, with the Scottish population suffering the highest prevalence in Europe. Disease-modifying therapies, including beta-interferon (IFN-ß), are increasingly used to minimise relapse frequency in the majority of patients who present with a relapsing-remitting disease pattern. Unfortunately, neutralising antibodies (NABs) may develop against IFN-ß and are associated with reduced efficacy. These antibodies may be detected using a serum sample. Despite the importance of this problem, from both a patient's perspective and a wider community and economic standpoint, there is no universally agreed protocol for the use of NAB testing. Authorities variously suggest routine 'screening' testing or, conversely, testing only in specific situations. In Scotland, routine testing is seldom used. We report our experience of routine NAB testing in 105 patients (of whom 35 were NAB-positive) over two years in NHS Tayside and comment on its cost and implications.

The fiscal consequences of public health investments in disease-modifying therapies for the treatment of multiple sclerosis in Sweden.

Background and aims: The economic consequences of multiple sclerosis (MS) are broader than those observed within the health system. The progressive nature suggests that people will not be able to live a normal productive life and will gradually require public benefits to maintain living standards. This study investigates the public economic impact of MS and how investments in disease-modifying therapies (DMTs) influence the lifetime costs to government attributed to changes in lifetime tax revenue and disability benefits based on improved health status linked to delayed disease progression.Methods: Disease progression rates from previous MS Markov cohort models were applied to interferon beta-1a, peginterferon beta-1a, dimethyl fumarate, and natalizumab using a public economic framework. The established relationship between expanded disability status scale and work-force participation, annual earnings, and disability rates for each DMT were applied. Subsequently, we assessed the effect of DMTs on discounted governmental costs consisting of health service costs, social insurance and disability costs, and changes in lifetime tax revenues.Results: Fiscal benefits attributed to informal care and community services savings for interferon beta-1a, peginterferon beta-1a, dimethyl fumarate, and natalizumab were SEK340,387, SEK486,837, SEK257,330, and SEK958,852 compared to placebo, respectively. Tax revenue gains linked to changes in lifetime productivity for interferon beta-1a, peginterferon beta-1a, dimethyl fumarate, and natalizumab were estimated to be SEK27,474, SEK39,659, SEK21,661, and SEK75,809, with combined fiscal benefits of cost savings and tax revenue increases of SEK410,039, SEK596,592, SEK326,939, and SEK1,208,023, respectively.Conclusion: The analysis described here illustrates the broader public economic benefits for government attributed to changes in disease status. The lifetime social insurance transfer costs were highest in non-treated patients, and lower social insurance costs were demonstrated with DMTs. These findings suggest that focusing cost-effectiveness analysis only on health costs will likely underestimate the value of DMTs.

Cost-effectiveness of disease-modifying therapies in the management of multiple sclerosis for the Medicare population.

OBJECTIVE: To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) for the management of multiple sclerosis (MS) compared to best supportive care in the United States. METHODS: Cost-effectiveness analysis was undertaken using a state transition model of disease natural history and the impact of DMTs for the representative Medicare beneficiary with MS. Costs and outcomes were evaluated from the health-care payer perspective using a 50-year time horizon. Natural history data were drawn from a longitudinal cohort study. The effectiveness of the DMTs was evaluated through a systematic review. Utility data were taken from a study of patients with clinically definite MS in Nova Scotia. Resource use and cost data were derived from the Sonya Slifka database and associated literature. RESULTS: When based on placebo-controlled evidence, the marginal cost-effectiveness of interferon beta (IFNß) and glatiramer acetate compared to best supportive care is expected to be in excess of $100,000 per quality-adjusted life-year gained. When evidence from head-to-head trials is incorporated into the model, the cost-effectiveness of 6 MIU IFNß-1a is expected to be considerably less favorable. Treatment discontinuation upon progression to Expanded Disability Status Scale 7.0 is expected to improve the cost-effectiveness of all DMTs. CONCLUSIONS: Further research is required to examine the long-term clinical effectiveness and cost-effectiveness of these therapies. There is no definitive guidance in the United States concerning discontinuation of DMTs; this study suggests that the prudent use of a treatment discontinuation rule may considerably improve the cost-effectiveness of DMTs.

Treating relapsing multiple sclerosis with subcutaneous versus intramuscular interferon-beta-1a: modelling the clinical and economic implications.

The EVIDENCE trial concluded that administering high-dose/high-frequency subcutaneous (SC) interferon-beta-1a (IFNb1a) was more effective in preventing relapses among patients with relapsing multiple sclerosis (MS) than low-dose weekly intramuscular (IM) IFNb1a after 64 weeks. This analysis utilized discrete-event simulation (DES) to model the potential longer-term clinical and economic implications of this trial. A DES predicting the course of relapsing MS and incorporating the effect of IFNb1a therapy was developed. The model began by randomly reading in actual patient data from the trial to create 1000 patients. Each simulated patient was replicated - one was assigned to receive SC IFNb1a three times a week and the other to receive IM IFNb1a once a week. During the simulation, patients may (i) experience relapses, with associated short- and long-term impacts on costs and disability; (ii) develop new T2 lesions detected by a magnetic resonance imaging scan; (iii) discontinue treatment because of adverse events or lack of response; (iv) advance to secondary progressive MS; or (v) die. Model inputs were mainly obtained from the EVIDENCE trial, but were taken from published literature if they could not be obtained from the trial. Direct medical costs ($US, year 2006 values) to the US payers were primarily obtained by updating a published cost analysis. Costs and benefits were discounted at 3% per annum. Extensive sensitivity analyses were conducted to test the robustness of the model results. Based on 100 replications of 1000 patient pairs over 4 years, SC IFNb1a was predicted to enable more patients to avoid relapse (216 vs 147). Total mean costs per patient (discounted) were $US79 890 with SC IFNb1a versus $US74 485 with IM administration, a net increase of $US5405 per patient. However, SC IFNb1a was estimated to prevent 0.50 relapses and save 23 relapse-free days per patient, yielding incremental cost-effectiveness ratios of $US10 755 per relapse prevented and $US232 per relapse-free day gained. Sensitivity analyses revealed that the result was most sensitive to the treatment efficacy, model time horizon and cost of IFNb1a treatment. Based on the results observed in the EVIDENCE trial, the model predicted that SC IFNb1a would yield greater health benefits over 4 years than IM IFNb1a, at a cost that would seem to be a reasonable trade-off.

Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system that primarily afflicts young adults. Approximately 400,000 people in the United States are affected by MS. Although several forms of MS exist, the most common course is known as relapsing-remitting MS (RRMS), which affects about 85% of MS patients. This form of MS is characterized by relapses of neurologic symptoms followed by periods of recovery. Progression of disease can lead to increasingly severe disability. Since the introduction of immunomodulatory biologic agents, such as interferon betas and glatiramer acetate, treatment has helped to change the course of the disease. Under budgetary constraints, health services payers are challenged to differentiate the economic value of these agents for formulary selection and/or placement. OBJECTIVE: The primary objective of this analysis was to evaluate the 2-year cost-effectiveness of 4 disease modifying drugs (DMDs) used as first-line treatment of RRMS: glatiramer acetate, interferon (IFN) Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b SC injection. METHODS: An Excel-based model was developed to compare the relative effectiveness and cost components of relapses, disability progression, and DMDs in the treatment of RRMS over a 2-year time horizon. The relative risk reduction (RRR) method was used to compare reduction in relapse rates and disease progression data from pivotal randomized double-blind placebo-controlled clinical trials of the DMDs. RRRs for relapses and disability progression, respectively, were calculated as the relative difference (treatment vs. placebo) in relapse rates and disease progression rates from placebo-controlled clinical trials. These RRRs were applied to the weighted average rates of relapse and number of disability progression steps seen in the placebo arms of the pivotal studies. The evaluation was conducted from the perspective of a U.S. health care payer (only direct medical costs considered). Medical savings were calculated as costs saved due to relapses avoided and prevention in disability progression steps. In the base case analysis, we assumed 89.4% persistence, a cost per relapse of $4,682, and a cost per disability progression step of $1,788. Monthly cost of therapy was defined as wholesale acquisition cost ($0 contractual discounts and $25 patient copayment assumed in the base case analysis) plus routine monitoring costs as assessed by an expert panel. The primary economic endpoint was cost per relapse avoided. Costs and outcomes occurring in the second year were discounted 3% to bring to 2008 present values. Oneway and multiway probabilistic (Monte Carlo) sensitivity analyses were conducted on key input variables to assess their impact on cost per relapse avoided. RESULTS: Without DMD treatment, patients were predicted to experience 2.55 relapses and 0.44 disability progression steps over a 2-year period (discounted values). The 2-year reductions in clinical relapses for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.66, 0.42, 0.74, and 0.70, respectively. The 2-year reductions in disability progression steps for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.05, 0.15, 0.12, and 0.11, respectively. In the base case analysis, IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate had the most favorable costs per relapse avoided ($80,589; $87,061; and $88,310; respectively) and IFN Beta-1a IM injection had the least favorable cost-effectiveness ratio ($141,721 per relapse avoided). Sensitivity analyses showed that these results were robust to changes in key input parameters, such as the number of relapses and disease progression steps in untreated patients, the RRR in clinical relapse and progression rates, the rate of persistence, the average cost of relapse, and the average cost of a disease progression step. CONCLUSION: This evaluation suggests that IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate represent the most cost-effective DMDs for the treatment of RRMS, where cost-effectiveness is defined as cost per relapse avoided, assuming that (a) the RRR in relapses and disease progression steps calculated from multiple DMD placebo-controlled clinical trials reflect real differences among DMDs over 2 years; and (b) resource unit costs derived from published sources reflect economic consequences of relapses and disease progression.

Cost-utility analysis of alemtuzumab in comparison with interferon beta, fingolimod, and natalizumab treatment for relapsing-remitting multiple sclerosis in Austria.

BACKGROUND: Multiple sclerosis (MS), a chronic progressive, demyelinating, inflammatory disease, affects 2.5 million people worldwide. Approximately 63% of cases are classified as relapsing-remitting MS (RRMS) at the time of diagnosis. The aim of this cost-utility analysis is to evaluate alemtuzumab vs interferon beta (intramuscular [IM] interferon beta-1a, subcutaneous [SC] interferon beta-1a, SC interferon beta-1b, and SC pegylated interferon beta-1a) in previously treated, and vs SC interferon beta-1a, fingolimod, and natalizumab in untreated RRMS patients to determine the incremental cost-effectiveness ratio among the treatment alternatives as prices, the route, and the frequency of administration of considered products vary significantly. METHODS: The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained). Markov modeling with a 10-year time horizon was carried out. During each 3-month cycle, patients maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS), or showed EDSS progression in SPMS; experienced relapses; suffered from an adverse event (AE); changed treatment; or died. A published network meta-analysis (NMA) was used for indirect comparison. The possibility of a therapy switch was considered. Clinical input data and resource utilization data were derived from the literature. Costs were extracted from price lists published in Austria and were calculated from the payer's perspective. RESULTS: In treatment naïve patients, alemtuzumab is associated with costs of €132,663 and 5.25 QALYs in a 10-year time horizon. Costs for SC interferon beta amount to €164,159 and generate 4.85 QALYs. Also, in the pre-treated patients, alemtuzumab dominated comparators by accumulating higher total QALYs (4.88) and lower total costs (€137.409) compared to interferon beta-1a (€200.133), fingolimod (€240.903), and natalizumab (€247.758). CONCLUSION: The analysis shows that alemtuzumab is a cost-saving alternative to treat RRMS in pre-treated and therapy naïve patients. From the patient perspective, alemtuzumab improves quality-of-life.

Cost analysis of therapy for patients with multiple sclerosis (MS) in Poland.

Multiple sclerosis (MS) is a neurological disease of the central nervous system in which dissipated demyelination lesions develop. The currently available pharmacotherapy and rehabilitation for this disease aims to preserve the patients' physical abilities and prevent disease progression and nervous system damage. The study evaluated the direct and indirect costs associated with two different treatment regimens for multiple sclerosis diagnosed patients by comparing two groups of 60 subjects (Group A--patients receiving continuous interferon therapy (Betaferon) and steroids during relapses, and Group B--patients receiving steroid-only (Solu-Medrol, Metypred) treatment). The study was conducted over two years (2004-2005). The pharmacotherapy costs for MS patients were: PLN 4,555,360.68 (1,171,043.88euro) total for Group A and PLN 75,922.68 (19,517.40euro) per patient, and PLN 72,582.00 (18,658.61euro) total for Group B and PLN 1,209.70 (310.98euro) per patient. Total direct and indirect costs for Group A and Group B amounted to PLN 5,595,968.58 (1,438,552.33euro) and PLN 1,655,658.30 (425,619.10euro), respectively.

Glatiramer acetate versus interferon beta-1a for subcutaneous administration: comparison of outcomes among multiple sclerosis patients.

INTRODUCTION: We compared the outcomes of multiple sclerosis (MS) patients treated with either glatiramer acetate (GA) (Copaxone, Teva Pharmaceutical Industries, Israel) or interferon beta-1a for subcutaneous administration (IFN beta-1a-SC) (Rebif, Merck Serono, Switzerland). METHODS: Data were obtained from i3's Lab Rx Database from July 2001 to June 2006. We established an 'intent-to-treat' (ITT) cohort (n=845) of patients diagnosed with MS who began therapy on either GA (n=542) or IFN beta-1a-SC (n=303) and had continuous insurance coverage from 6 months before to 24 months after the date they began taking the medication. We also created a 'continuous use' (CU) cohort (n=410) of individuals who, in addition to the criteria listed above, used either GA or IFN beta-1a-SC within 28 days of the end of the 2-year-post period. Using multivariate regressions, we examined both the 2-year total direct medical costs and the likelihood of relapse associated with the use of these two MS medications. We defined relapse as either being hospitalised with a diagnosis of MS, or being diagnosed with MS during an outpatient visit and then prescribed steroids within a 7-day period. All regressions controlled a wide range of factors that have potentially affected outcomes. RESULTS: In the ITT cohort, patients who started therapy on GA had a significantly lower 2-year risk of relapse (5.92% versus 10.89%; P=0.0305), as well as significantly lower 2-year total medical costs (US$41,786 versus US$49,030; P=0.0002). In the CU cohort, patients who used GA also had a significantly lower 2-year risk of relapse (1.94% versus 9.09%; P=0.0049) and significantly lower total medical costs (US$45,213 versus US$57,311; P<0.0001). CONCLUSIONS: Results indicate that, compared with the use of IFN beta-1a-SC, use of GA is associated with significantly lower probability of relapse as well as significantly lower 2-year total direct medical costs. In addition, these results are more pronounced among patients defined as continuous users.

Cost-effectiveness of four immunomodulatory therapies for relapsing-remitting multiple sclerosis: a Markov model based on long-term clinical data.

BACKGROUND: Before the introduction of the immunomodulatory therapies for multiple sclerosis (MS), treatment options for MS consisted of symptomatic management (physical therapy and pharmacological treatment for symptom management). Symptomatic management for MS has been supplemented in the past decade by 2 new classes of immunomodulatory therapies that have been approved as first-line treatments for relapsing-remitting multiple sclerosis (RRMS): subcutaneous glatiramer acetate (SC GA) and 3 beta-interferons: intramuscular interferon beta-1a (IM IFNbeta-1a), SC IFNbeta-1a, and SC IFNbeta-1b. OBJECTIVE: To estimate the economic outcomes of 5 treatment strategies: symptom management alone, symptom management combined with SC GA, IM IFNbeta1-a, SC IFNbeta1-a, or SC IFNbeta1-b in patients diagnosed with RRMS. METHODS: A literature-based Markov model was developed to assess the cost-effectiveness of 5 treatment strategies for managing a hypothetical cohort of patients diagnosed with RRMS in the United States--4 immunomodulatory drug therapies and symptom management alone. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS), a widely accepted scale for assessing RRMS (higher EDSS scores = increased disease severity). Baseline relapse and disease progression transition probabilities for symptom management were obtained from natural history studies. Treatment effects of the immunomodulatory therapies were estimated by applying a percentage reduction to the symptom management transition probabilities for relapse (27% reduction) and disease progression (30% reduction). Transition probabilities were subsequently adjusted to account for (1) the effects of neutralizing antibodies, specifically on relapse rates by assuming no additional therapy benefits after the second year of continuous therapy, and (2) treatment discontinuation. Therapy-specific data were obtained from clinical trials and long-term follow-up observational studies. Transitions among health states occurred in 1-month cycles for the lifetime of a patient. Costs (2005 US$) and outcomes were discounted at 3% annually. RESULTS: The incremental cost per quality-adjusted life-year for the 4 immunomodulatory therapies is $258,465, $303,968, $416,301, and $310,691 for SC GA, IM IFNbeta-1a, SC IFNbeta-1a, and SC IFNbeta-1b, respectively, compared with symptom management alone. Sensitivity analyses demonstrated that results were sensitive to changes in utilities, disease progression rates, time horizon, and immunomodulatory therapy cost. CONCLUSIONS: The pharmacoeconomic model determined that SC GA was the best strategy of the 4 immunomodulatory therapies used to manage MS and resulted in better outcomes than symptom management alone. Sensitivity analyses indicated that the model was sensitive to changes in a number of key parameters, and thus changes in these key parameters would likely influence the estimated cost-effectiveness results. Head-to-head randomized clinical trials comparing the immunomodulatory therapies for the treatment of MS are necessary to validate the projections from the pharmacoeconomic analyses, particularly since the results available today from the clinical trials do not account adequately for treatment dropouts.

Peginterferon beta-1a versus other self-injectable disease-modifying therapies in the treatment of relapsing-remitting multiple sclerosis in Scotland: a cost-effectiveness analysis.

AIMS: Peginterferon beta-1a 125 mcg administered subcutaneously every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved in January 2015 by the Scottish Medicines Consortium. This study assesses long-term clinical and economic outcomes of peginterferon beta-1a compared with other self-injectable DMTs (interferon beta-1a [22 mcg, 30 mcg, and 44 mcg], interferon beta-1b, and glatiramer acetate 20 mg) in the treatment of RRMS, from the National Health Service and Personal Social Services perspective in Scotland. METHODS: A previously published, validated Markov cohort model was adapted for this analysis. The model estimates changes in patient disability, occurrence of relapses, and other adverse events, and translates them into quality-adjusted life years and costs. Natural history data came from the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database, and a large population-based MS survey in the UK. The comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (2015 British Pounds) were obtained from public databases and literature. Clinical and economic outcomes were projected over 30 years and discounted at 3.5% per year. RESULTS: Over 30 years, peginterferon beta-1a was dominant compared with interferon beta-1a (22, 30, and 44 mcg), and interferon beta-1b, and cost-effective compared with glatiramer acetate 20 mg. Results were most sensitive to variations in each DMT's efficacy and acquisition costs. Deterministic and probabilistic sensitivity analyses confirmed the robustness of the results. LIMITATIONS: The impact of improved adherence with peginterferon beta-1a on clinical and economic outcomes and the impact of subsequent DMTs after treatment discontinuation were not considered. Oral and infused DMTs were not included as comparators. Conclusion Long-term treatment with peginterferon beta-1a improves clinical outcomes, while its cost profile makes it either dominant or cost-effective compared with other self-injectable DMTs for the treatment of RRMS in Scotland.

Cost-Effectiveness of Peginterferon Beta-1a and Alemtuzumab in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, affecting 2.5 million people globally and 400,000 people in the United States. While no cure exists for MS, the goal is to manage the disease using disease-modifying therapies (DMTs), which have been shown to slow disease progression and prevent relapses. Relapsing-remitting MS (RRMS) is the most common form of MS at the time of diagnosis. Peginterferon beta-1a (PEG) and alemtuzumab (ALT) were recently approved and have demonstrated good clinical outcomes, including reduced relapse rates in clinical trials. High costs associated with these DMTs necessitates cost-effectiveness analyses to understand their overall value in RRMS management. OBJECTIVES: To assess the cost-effectiveness of (a) Model 1: PEG relative to intramuscular interferon beta-1a (IM IFN), subcutaneous interferon beta-1b (SC IFN), glatiramer acetate 20 mg per mL (GA), fingolimod (FIN), natalizumab (NAT), and dimethyl fumarate (DMF), and (b) Model 2: ALT relative to subcutaneous interferon beta-1a 44 µg (IFN beta-1a 44 µg). Both analyses were conducted from a U.S. third-party payer perspective. METHODS: Two static decision models were used to compare the cost-effectiveness of PEG and ALT over a 1-year and a 2-year time horizon, respectively. Model inputs were drug acquisition costs (wholesale acquisition cost from RED BOOK); drug administration and monitoring costs (package inserts and Centers for Medicare & Medicaid Services 2015 Physician Fee Schedule); relapse rates and relapse rate reduction (clinical trials); and cost of managing relapses (published literature). All costs were adjusted to 2015 U.S. dollars using the medical care component of the Consumer Price Index. Outcomes measured were total cost of therapy per patient, cost per relapse avoided, and incremental cost-effectiveness ratios (ICERs) calculated as cost per relapse avoided. Sensitivity analysis was conducted to test model robustness given the uncertainty of model inputs and study assumptions. RESULTS: Model 1 results showed that PEG dominated IM IFN and GA, compared with SC IFN; PEG had an ICER of $1,978,000 per relapse avoided. Compared with FIN, NAT, and DMF, PEG was less expensive and less effective. Model 2 showed that ALT had an ICER of $25,276 per relapse avoided relative to IFN beta-1a 44 µg. CONCLUSIONS: In patients with RRMS, PEG is a viable alternative when compared with the DMTs in our model. Deciding whether to choose PEG over other DMTs would depend on multiple factors. On the other hand, ALT had an ICER of $25,276 cost per relapse avoided relative to IFN beta-1a 44 µg. The study results will assist payers in evaluating different medication choices for effective therapy. DISCLOSURES: No outside funding supported this study. Kamal has received research funding from Novartis Pharmaceuticals and the College of Psychiatric and Neurologic Pharmacists and also serves as a consultant for the Lynx Group. Dashputre and Pawar report no conflicts of interest. Study concept and design were primarily contributed by Dashputre, along with Kamal and Pawar. Dashputre took the lead in data collection, along with Kamal, and data analysis was performed by Dashputre, Kamal, and Pawar. The manuscript was written and revised primarily by Dashputre, along with Kamal and Pawar.

Good practice guidelines for decision-analytic modelling in health technology assessment: a review and consolidation of quality assessment.

The use of decision-analytic modelling for the purpose of health technology assessment (HTA) has increased dramatically in recent years. Several guidelines for best practice have emerged in the literature; however, there is no agreed standard for what constitutes a 'good model' or how models should be formally assessed. The objective of this paper is to identify, review and consolidate existing guidelines on the use of decision-analytic modelling for the purpose of HTA and to develop a consistent framework against which the quality of models may be assessed. The review and resultant framework are summarised under the three key themes of Structure, Data and Consistency. 'Structural' aspects relate to the scope and mathematical structure of the model including the strategies under evaluation. Issues covered under the general heading of 'Data' include data identification methods and how uncertainty should be addressed. 'Consistency' relates to the overall quality of the model. The review of existing guidelines showed that although authors may provide a consistent message regarding some aspects of modelling, such as the need for transparency, they are contradictory in other areas. Particular areas of disagreement are how data should be incorporated into models and how uncertainty should be assessed. For the purpose of evaluation, the resultant framework is applied to a decision-analytic model developed as part of an appraisal for the National Institute for Health and Clinical Excellence (NICE) in the UK. As a further assessment, the review based on the framework is compared with an assessment provided by an independent experienced modeller not using the framework. It is hoped that the framework developed here may form part of the appraisals process for assessment bodies such as NICE and decision models submitted to peer review journals. However, given the speed with which decision-modelling methodology advances, there is a need for its continual update.

Cost-effectiveness analysis of peginterferon beta-1a compared with interferon beta-1a and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis in the United States.

Objective Peginterferon beta-1a 125 mcg, administered subcutaneously (SC) every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved by the US Food and Drug Administration in 2014. This study assesses the cost-effectiveness of peginterferon beta-1a vs interferon beta-1a (44 mcg SC 3 times per week) and glatiramer acetate (20 mg SC once-daily) in the treatment of RRMS from the perspective of a US payer over 10 years. Methods A Markov cohort economic model was developed for this analysis. The model predicts disability progression, occurrence of relapses and other adverse events and translates them into quality-adjusted life years (QALYs) and costs. Natural history data were obtained from the placebo arm of the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database and a large population-based MS survey. Comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (in 2014 US dollars) were sourced from public databases and literature. Clinical and economic outcomes were discounted at 3% per year. Results Over 10 years, peginterferon beta-1a was dominant (i.e., more effective and less costly), with cost-savings of $22,070 and additional 0.06 QALYs when compared with interferon beta-1a 44 mcg and with cost-savings of $19,163 and 0.07 QALYs gained when compared with glatiramer acetate 20 mg. Results were most sensitive to variations in the treatment effect of each DMT, treatment acquisition costs of each DMT and the time horizon. Probabilistic sensitivity analyses indicated that peginterferon beta-1a remains dominant in >90% of 5,000 replications compared with either DMTs. Conclusion This analysis suggests that long-term treatment with peginterferon beta-1a improves clinical outcomes at reduced costs compared with interferon beta-1a 44 mcg and glatiramer acetate 20 mg and should be a valuable addition to managed care formularies for treating patients with RRMS.

Subcutaneous recombinant interferon-beta-1a (Rebif): a review of its use in relapsing-remitting multiple sclerosis.

Subcutaneous recombinant interferon-beta-1a (Rebif) 22 or 44 microg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). It has shown benefits on outcome measures related to relapses, progression of disability and magnetic resonance imaging (MRI) in clinical trials. A significant efficacy advantage for subcutaneous interferon-beta-1a three times weekly over intramuscular interferon-beta-1a 30 microg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-beta-1a 44 microg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS.

[Cost-utility analysis of relapsing-remitting multiple sclerosis treatment with azathioprine or interferon beta in Spain]. / Análisis coste-utilidad del tratamiento de la esclerosis múltiple remitente-recidivante con azatioprina o interferón beta en España.

AIM: To carry out a cost-utility analysis of the treatment of relapsing-remitting multiple sclerosis (RRMS) with azathioprine (Imurel) or beta interferon (all, Avonex, Rebif and Betaferon). MATERIAL AND METHODS: Pharmacoeconomic Markov model comparing treatment options by simulating the life of a hypothetical cohort of women aged 30, from the societal perspective. The transition probabilities, utilities, resource utilisation and costs (direct and indirect) were obtained from Spanish sources and from bibliography. Univariant sensitivity analyses of the base case were performed. RESULTS: In the base case analysis, the average cost per patient (euros in 2003) of a life treatment, considering a life expectancy of 53 years, would be 620,205, 1,047,836, 1,006,014, 1,161,638 and 968,157 euros with Imurel, all interferons, Avonex, Rebif and Betaferon, respectively. Therefore, the saving with Imurel would range between 327,000 and 520,000 euros approximately. The quality-adjusted life years (QALY) obtained with Imurel or interferons would be 10.08 and 9.30, respectively, with an average gain of 0.78 QALY per patient treated with Imurel. The sensitivity analyses confirmed the robustness of the base case. The cost of one additional QALY with interferons would range between 413,000 and 1,308,000 euros approximately in the hypothetical worst scenario for Imurel. CONCLUSIONS: For a typical patient with RRMS, treatment with Imurel would be more efficient than interferons and would dominate (would be more efficacious with lower costs) beta interferon.

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.

BACKGROUND: In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada. METHODS: In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective. FINDINGS: 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4-80·2]; multilevel model, 60·0% [56·6-63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2-62·8]; multilevel model, 57·1% [53·0-61·2]). INTERPRETATION: Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible. FUNDING: Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme.

Cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate and intramuscular interferon-ß1a in relapsing-remitting multiple sclerosis.

OBJECTIVE: The aim of the study was to compare the cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and intramuscular (IM) interferon (IFN)-ß(1a) as first-line therapies in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A Markov model was developed to evaluate the cost effectiveness of disease-modifying drugs (DMDs) from a US societal perspective. The time horizon in the base case was 5 years. The primary outcome was incremental net monetary benefit (INMB), and the secondary outcome was incremental cost-effectiveness ratio (ICER). The base case INMB willingness-to-pay (WTP) threshold was assumed to be US$150,000 per quality-adjusted life year (QALY), and the costs were in 2012 US dollars. One-way sensitivity analyses and probabilistic sensitivity analysis were conducted to test the robustness of the model results. RESULTS: Dimethyl fumarate dominated all other therapies over the range of WTPs, from US$0 to US$180,000. Compared with IM IFN-ß(1a), at a WTP of US$150,000, INMBs were estimated at US$36,567, US$49,780, and US$80,611 for fingolimod, teriflunomide, and dimethyl fumarate, respectively. The ICER of fingolimod versus teriflunomide was US$3,201,672. One-way sensitivity analyses demonstrated the model results were sensitive to the acquisition costs of DMDs and the time horizon, but in most scenarios, cost-effectiveness rankings remained stable. Probabilistic sensitivity analysis showed that for more than 90% of the simulations, dimethyl fumarate was the optimal therapy across all WTP values. CONCLUSION: The three oral therapies were favored in the cost-effectiveness analysis. Of the four DMDs, dimethyl fumarate was a dominant therapy to manage RRMS. Apart from dimethyl fumarate, teriflunomide was the most cost-effective therapy compared with IM IFN-ß(1a), with an ICER of US$7,115.

New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis.

PURPOSE: Interferon injectables and glatiramer acetate have served as the primary disease-modifying treatments for multiple sclerosis (MS) since their introduction in the 1990s and are first-line treatments for relapsing-remitting forms of MS (RRMS). Many new drug therapies were launched since early 2010, expanding the drug treatment options considerably in a disease state that once had a limited treatment portfolio. The purpose of this review is to critically evaluate the safety profile and efficacy data of disease-modifying agents for MS approved by the US Food and Drug Administration (FDA) from 2010 to the present and provide cost and available pharmacoeconomic data about each new treatment. METHODS: Peer-reviewed clinical trials, pharmacoeconomic studies, and relevant pharmacokinetic/pharmacologic studies were identified from MEDLINE (January 2000-December 2014) by using the search terms multiple sclerosis, fingolimod, teriflunomide, alemtuzumab, dimethyl fumarate, pegylated interferon, peginterferon beta-1a, glatiramer 3 times weekly, and pharmacoeconomics. Citations from available articles were also reviewed for additional references. The databases publically available at www.clinicaltrials.gov and www.fda.gov were searched for unpublished studies or studies currently in progress. FINDINGS: A total of 5 new agents and 1 new dosage formulation were approved by the FDA for the treatment of RRMS since 2010. Peginterferon beta-1a and high-dose glatiramer acetate represent 2 new effective injectable options for MS that reduce burden of administration seen with traditional interferon and low-dose glatiramer acetate. Fingolimod, teriflunomide, and dimethyl fumarate represent new oral agents available for MS, and their efficacy in reducing annualized relapse rates is 48% to 55%, 22% to 36.3%, and 44% to 53%, respectively, compared with placebo. Alemtuzumab is a biologic given over a 2-year span that reduced annualized relapse rates by 55% in treatment-naive patients and by 49% in patients relapsing on prior disease-modifying agents. Treatment emergent adverse effects were common with all new drug treatments. The cost of treating MS remains high, because MS therapies accounted for the highest spending growth of any specialty drug class in 2013. Most therapies cost, on average, US $6000/mo based on wholesale acquisition cost, and few cost-benefit studies are available for new treatments. IMPLICATIONS: With expansion of new treatments, patients and providers now have multiple options and improved flexibility in managing MS. The relative place in therapy of new treatments is unknown, and treatment decisions are largely based on patient preference, efficacy, and risk potential. The cost of treating MS continues to be high, even with more treatment options available.