Economic burden of highly active relapsing-remitting multiple sclerosis patients in the French national health insurance database.

BACKGROUND: As healthcare management of highly active-relapsing-remitting multiple sclerosis (HA-RRMS) patients is more complex than for the whole multiple sclerosis (MS) population, this study assessed the related economic burden from a National Health Insurance's (NHI's) perspective. RESEARCH DESIGN AND METHODS: Study based on French NHI databases, using individual data on billing and reimbursement of outpatient and hospital healthcare consumption, paid sick leave and disability pension, over 2010-2017. RESULTS: Of the 9,596 HA-RRMS adult patients, data from 7,960 patients were analyzed with at least 2 years of follow-up. Mean annual cost/patient was €29,813. Drugs represented 40% of the cost, hospital care 33%, disability pensions 9%, and all healthcare professionals' visits combined 8%. Among 3,024 patients under 60 years-old with disability pension, disability pension cost €7,168/patient/year. Among 3,807 patients with paid sick leave, sick leave cost €1,956/patient/year. Mean costs were €2,246/patient higher the first year and increased by €1,444 between 2010 and 2015, with a €5,188 increase in drug-related expenditures and a €634 increase in healthcare professionals' visits expenditures but a €4,529 decrease in hospital care expenditures. CONCLUSIONS: The cost of health care sick leaves, and disability pensions of HA-RRMS patients was about twice as high as previously reported cost of MS patients.

Improving quality, affordability, and equity of multiple sclerosis care.

OBJECTIVE: The prevailing approaches to selecting multiple sclerosis (MS) disease modifying therapies (DMTs) have contributed to exponential increases in societal expenditures and out-of-pocket expenses, without compelling evidence of improved outcomes. Guidance is lacking regarding when and in whom the benefits of preventing MS-related disability likely outweighs the risks of highly effective DMTs (HET) and when it is appropriate to consider DMT costs. Our objective was to develop a standardized approach to improve the quality, affordability and equity of MS care. METHODS: MS experts partnered with health plan pharmacists to develop an ethical, risk-stratified, cost-sensitive treatment algorithm. We developed a risk-stratification schema to classify patients with relapsing forms of MS as high, intermediate or low risk of disability based on the best available evidence and, when the evidence was poor or lacking, by consensus. DMTs are grouped as highly, modestly or low/uncertain effectiveness and preferentially ranked within groups by safety based on pre-specified criteria. We reviewed FDA documents and the published literature. When efficacy and safety are equivalent, the lower cost DMT is preferred. RESULTS: Assignment to the high-risk group prompts treatment with preferred HETs early in the disease course. For persons in the intermediate- or low-risk groups with cost or health care access barriers, we incorporated induction therapy with an affordable B-cell depleting agent. Based on more favorable safety profiles, our preferred approach prioritizes use of rituximab and natalizumab among HETs and interferon-betas or glatiramer acetate among modestly effective agents. INTERPRETATION: The risk-stratified treatment approach we recommend provides clear, measurable guidance in whom and when to prescribe HETs, when to prioritize lower cost DMTs and how to accommodate persons with MS with cost or other barriers to DMT use. It can be adapted to other cost structures and updated quickly as new information emerges. We recommend that physician groups partner with health insurance plans to adapt our approach to their settings, particularly in the United States. Future studies are needed to resolve the considerable uncertainty about how much variability in prognosis specific risk factors explain.

Long-term Socioeconomic Outcomes Associated With Pediatric-Onset Multiple Sclerosis.

Importance: Pediatric-onset multiple sclerosis (PoMS) is associated with significant cognitive and physical disability. Whether this disability translates into differences in educational achievements and earnings is unknown. Objective: To evaluate the association between PoMS and educational level and income throughout adulthood. Design, Setting, and Participants: A prospective register-based cohort study of individuals with PoMS and a population-based matched reference cohort was conducted using nationwide microdata from linked registers in Sweden from January 1, 1990, to December 31, 2016; analyses were completed from May 1, 2019, to September 1, 2020. Of 772 persons with PoMS identified in the Swedish MS registry, 485 had an onset during the period from 1980 to 2014 and had socioeconomic data available. The general population reference cohort without multiple sclerosis (MS) (n = 4850) was randomly selected from the full Swedish population, matched 10:1 on age, sex, and country of birth. Exposure: Pediatric-onset MS, diagnosed by a neurologist, with onset before 18 years of age. Main Outcomes and Measures: Highest educational level (elementary school, high school, or university) was assessed using logistic regression. Income, measured as the mean annual earnings from paid work in US dollars, was compared using Tobit models, and net annual sickness absence and disability pension days were compared using zero-inflated negative binomial regression. Earnings and days receiving disability benefits were compared within 4 age periods (19-24, 25-34, 35-44, and 45-54 years). Results: The median age of the cohort with PoMS (n = 485) and the matched reference cohort (n = 4850) in 2016 was 32 years (interquartile range, 26-40 years), and most participants were women (348 [71.8%] in the PoMS cohort and 3480 [71.8%] in the matched reference cohort). Persons with PoMS were less likely than persons in the matched reference cohort to attend university (odds ratio, 0.80 [95% CI, 0.66-0.97]) and had significantly lower annual earnings than the reference cohort, ranging from -$1618 (95% CI, -$2558 to -$678) in the youngest age period to -$10 683 (95% CI, -$18 187 to -$3178) in the eldest. Persons with PoMS received higher rates of disability benefits, as sickness absence days in the youngest age period (rate ratio, 3.06 [95% CI, 2.08-4.52]) and disability pension days in the oldest age period (rate ratio, 1.43 [95% CI, 1.11-1.85]). Conclusions and Relevance: This study suggests that having PoMS is associated with less educational achievement, lower earnings, and greater use of disability benefits throughout the working-age life span. As adults, persons with PoMS never earned as much as their counterparts without MS, and they exhibited a heavier reliance on disability benefits.

Exploring the Cost Effectiveness of Shared Decision Making for Choosing between Disease-Modifying Drugs for Relapsing-Remitting Multiple Sclerosis in the Netherlands: A State Transition Model.

BACKGROUND: Up to 31% of patients with relapsing-remitting multiple sclerosis (RRMS) discontinue treatment with disease-modifying drug (DMD) within the first year, and of the patients who do continue, about 40% are nonadherent. Shared decision making may decrease nonadherence and discontinuation rates, but evidence in the context of RRMS is limited. Shared decision making may, however, come at additional costs. This study aimed to explore the potential cost-effectiveness of shared decision making for RRMS in comparison with usual care, from a (limited) societal perspective over a lifetime. METHODS: An exploratory economic evaluation was conducted by adapting a previously developed state transition model that evaluates the cost-effectiveness of a range of DMDs for RRMS in comparison with the best supportive care. Three potential effects of shared decision making were explored: 1) a change in the initial DMD chosen, 2) a decrease in the patient's discontinuation in using the DMD, and 3) an increase in adherence to the DMD. One-way and probabilistic sensitivity analyses of a scenario that combined the 3 effects were conducted. RESULTS: Each effect separately and the 3 effects combined resulted in higher quality-adjusted life years (QALYs) and costs due to the increased utilization of DMD. A decrease in discontinuation of DMDs influenced the incremental cost-effectiveness ratio (ICER) most. The combined scenario resulted in an ICER of €17,875 per QALY gained. The ICER was sensitive to changes in several parameters. CONCLUSION: This study suggests that shared decision making for DMDs could potentially be cost-effective, especially if shared decision making would help to decrease treatment discontinuation. Our results, however, may depend on the assumed effects on treatment choice, persistence, and adherence, which are actually largely unknown.

Disease-Modifying Therapy Adherence and Associated Factors in a National Sample of Medicare Patients With Multiple Sclerosis.

OBJECTIVES: Disease-modifying therapies (DMTs) reduce relapse rates and disability progression for relapsing multiple sclerosis (MS). Although 25% to 30% of all US patients with MS are Medicare beneficiaries, limited information exists on this population. This is the first study using national Medicare data to (1) describe characteristics of patients with MS using DMTs, (2) estimate adherence to DMTs over a 1-year and 3-year follow-up, and (3) examine factors associated with DMT adherence. METHODS: This retrospective claims analysis used 2011-2014 100% Medicare files. Monthly adherence to MS DMTs was defined as the proportion of days covered ≥0.80 with any DMT in each month for 1-year (n = 36 593) and 3-year (n = 17 599) follow-up samples of MS DMT users. Generalized estimating equation logistic regressions were used to estimate factors associated with adherence to DMTs. RESULTS: Over 90% of patients were eligible for Medicare owing to disability, and about three-quarters qualified for low-income subsidies. A downward trend in DMT adherence was observed over time in both samples. Monthly adherence dropped significantly between December of the prior year to January of the following year (from 76% to 65% in the 1-year follow-up sample and similar drops seen across all years in the 3-year follow-up sample). Multivariable regressions indicated characteristics such as being low-income, having a disability, and having high patient out-of-pocket DMT costs associated with poor adherence to DMTs. CONCLUSION: Our study provides important insights into the characteristics and DMT adherence of Medicare patients with MS and highlights the need for interventions and policies mitigating barriers to adherence in this population.

Cost-effectiveness of Cladribine Tablets and fingolimod in the treatment of relapsing multiple sclerosis with high disease activity in Spain.

OBJECTIVE: To estimate the cost-effectiveness of Cladribine Tablets in the treatment of relapsing multiple sclerosis (RMS) with high disease activity compared with fingolimod, from the perspective of the National Health System (NHS) in Spain. METHODS: A Markov model was developed. The annual transition probabilities, were adjusted to patients with RMS with high disease activity. The effect of the treatments compared on the Expanded Disability Status Scale (EDSS) was modeled by hazard ratios for the confirmed progression of disability. The annual relapse rate and the probability of suffering adverse reactions were obtained from a meta-analysis and the literature. The derived costs were calculated from Spanish unit costs. The utilities were obtained from the CLARITY clinical trial and the literature. Deterministic and probabilistic sensitivity analyzes were performed. RESULTS: Cladribine tablets was the dominant treatment: lower costs (-86,536 €) and more effective (+1.11 quality-adjusted life years - QALYs) compared to fingolimod. The probability that Cladribine Tablets was cost-effective compared to fingolimod ranged between 94.6% and 96.1% for willingness to pay from € 20,000 to € 30,000 per QALY gained. CONCLUSIONS: Cladribine Tablets is a cost-effective treatment, compared to fingolimod, for the treatment of RMS with high disease activity. EXPERT OPINION: According to the present study, compared to fingolimod, treatment with Cladribine Tablets of relapsing multiple sclerosis with high disease activity is an option that could generate savings for the Spanish National Health System, with a considerable gain in QALYs. Cladribine Tablets is considered cost-effective and dominant (less costs and more effectiveness) than fingolimod treatment option in this population.

Differentiating societal costs of disability worsening in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), confirmed disability progression (CDP) can be either the result of progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). However, the economic effect of PIRA and RAW on societal economic costs in patients with MS is not well understood. OBJECTIVE: To determine societal economic costs of patients achieving disease activity free status (DAF) and compare them with those having PIRA and RAW events. METHODS: We used a roving EDSS score analysis to detect PIRA and RAW events with confirmation after at least 6 months. We estimated the age-, gender-, EDSS-adjusted effects of PIRA and RAW on total, direct medical, direct non-medical and indirect societal economic costs. Patients achieving DAF were assigned to as reference. RESULTS: Overall, 1959 patients were analyzed. Total mean quarterly societal economic costs including disease-modifying therapies (DMTs) were 6929€ (SD: 2886€) per patient averaged over a period of 2 years. Excluding DMTs, patients achieving DAF had total mean quarterly costs of 1703€ (SD: 2489€). PIRA caused 29% (IRR: 1.29; CI 1.06-1.50, p < 0.05) higher total costs compared to DAF. On the contrary, RAW increased total costs by factor 1.56 (CI 1.30-1.87, p < 0.001). The effect of PIRA and RAW was striking for direct medical costs which increased by factor 1.48 (95% CI 1.13-1.95, p < 0.01) and 2.25 (95% CI 1.72-2.94, p < 0.001), respectively. CONCLUSION: Disease progression increases societal economic costs significantly. Thus, delaying or even preventing disease progression in MS may reduce the societal economic burden of MS.

The impact of diagnostic criteria and treatments on the 20-year costs for treating relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess whether the introduction of the new diagnostic criteria and disease modifying therapies (DMTs) is associated with higher cost for treating multiple sclerosis (MS). METHODS: This is a regression-based quasi-experimental study employing interrupted time series analysis, including data from 2229 patients (age 42.1 ±â€¯11.2 years; female 63.34%), with incident diagnosis of relapsing remitting MS (RRMS) and followed up from 1997 to 2017, extracted from the database of the MS Clinical Care and Research Centre of the Federico II University Hospital of Naples (Italy). Annual healthcare costs for DMT (e.g., prescription, staff involved in DMT administration) and management (e.g., neurological consultations, other consultations related to DMT safety, MRI, laboratory exams), were calculated and inflated to the most recent value. RESULTS: Annual costs per patient for DMT prescription and management were not affected by the introduction of 2001 and 2005 criteria, but decreased by 0.4% after the introduction of 2011 criteria (PD= -0.4%; 95% C.I. -0.7%/-0.0%; p = 0.023). Annual costs per patient increased by 11.2% after the introduction of Natalizumab in 2007 (PD= 11.2%; 95% C.I.= 9.4%/13.0%; p <0.001), by 10.9% after the introduction of tablets in 2011 (Fingolimod, Teriflunomide and Dimethyl Fumarate) (PD= 10.9%; 95% C.I. 9.2%/12.7%; p<0.001), and by 10.7% after the introduction of Alemtuzumab in 2015 (PD= 10.7%; 95% C.I. 9.0%/12.4%; p< 0.001). DISCUSSION: DMTs remain the main responsible for increased medical direct costs in MS, whilst improved diagnostic skills and subsequent patient profiling can at least in part mitigate costs for MS treatment and management.

Cost Assessment Modelling of Treatments for Highly Active Relapsing Multiple Sclerosis.

INTRODUCTION: Cost assessment modelling (CAM) of treatments in highly active relapsing multiple sclerosis was conducted. METHODS: The CAM was developed using the R programming language. The PICOSTEPS health technology assessment framework was applied in the CAM. Modelled patients were 280 adults with highly active relapsing multiple sclerosis eligible for disease-modifying treatment. Intervention was cladribine tablets, a new and reimbursed oral treatment for highly active relapsing multiple sclerosis in Finland. Comparators included fingolimod, the most used oral reimbursed treatment for the highly active disease, and natalizumab, the most used intravenous treatment, and a treatment mix (80% use fingolimod, 20% use natalizumab) in Finland. Outcomes presented expected annual and cumulative drug-associated costs in the overall population and per patient. Setting was modelled public specialist care in Finland. Time was set to 4 years, without discounting. Effects covered expected drug-associated costs (screening, acquisition, administration, monitoring, adverse events, travelling, productivity). Perspective was a limited societal perspective. Sensitivity analyses regarding all PICOSTEPS components were conducted. RESULTS: Cladribine tablets were projected to be cost saving in comparison to fingolimod, natalizumab and treatment mix. The respective modelled savings were €4,598,742, €16,249,701 and €6,928,934 in the overall population, and €16,424, €58,035 and €24,746 per patient, respectively, during the 4 years. The most important cost driver was drug costs, representing 96.3%, 96.0% and 83.4% of modelled costs associated with cladribine tablets, fingolimod and natalizumab, respectively. Cladribine tablets sustained their affordability in the sensitivity analyses. From the perspective of health care payer, cladribine tablets' savings were projected to be €4,514,509, €15,145,366 and €6,640,680 in the overall population, and €16,123, €54,091 and €23,717 per patient in comparison to fingolimod, natalizumab and treatment mix, respectively. CONCLUSION: Based on the CAM, cladribine tablets were projected to robustly save modelled drug-associated costs in comparison to fingolimod, natalizumab and their mix in Finland.

Evaluating dalfampridine for the treatment of relapsing-remitting multiple sclerosis: does it add to the treatment armamentarium?

Introduction: Multiple sclerosis (MS) is a demyelinating disease, causing axonal damage and disability. Dalfampridine (DAL) is an extended-release formulation of 4-aminopyridine (4AP) and broad-spectrum voltage-dependent potassium channel blocker that is reported to improve motor, visual and cognitive functions. Furthermore, it is presently the only approved drug for walking impairment in MS. Areas covered: Herein, the authors evaluate DAL as a relapsing-remitting MS treatment, reporting and commenting on all aspects of the drug including its chemistry, safety, pharmacokinetics, and cost-effectiveness. A bibliographic search was performed on PubMed using the terms 'dalfampridine OR fampridine OR 4-aminopyridine'. Expert opinion: Evidence from post-marketing studies suggests that DAL, consistent with the effects of 4AP, may not only improve walking speed, but also arm function, fatigue, mood and cognition through restored nerve conduction in central nervous system demyelinated areas. Long-term safety data confirm that the approved dose of 10 mg twice daily is generally well tolerated. However, despite the reported efficacy, the extent of the benefits is limited in real life activities, although significant improvements have been demonstrated in the clinical setting. Patients often complain of side effects (such as cramps and painful paraesthesia) or lack of efficacy. Also, its considerably higher pricing in comparison to 4AP represents an important limitation.

Cost-effectiveness analysis of escalating to natalizumab or switching among immunomodulators in relapsing-remitting multiple sclerosis in Italy.

BACKGROUND: Published literature suggests that early treatment with natalizumab ("escalation strategy") is more effective than switch within the same class of immunomodulators (interferons/glatiramer acetate, "switching strategy") in relapsing-remitting multiple sclerosis (RRMS) patients who failed first-line self-injectable disease-modifying treatment (DMT). The present analysis aims to evaluate the cost-effectiveness profile of escalation strategy vs. switching strategy, adopting the Italian societal perspective. METHODS: A lifetime horizon Markov model was developed to compare early escalation to natalizumab vs. switching among immunomodulators, followed by subsequent escalation to natalizumab. The two compared treatment algorithms were: a) early escalation until progression to Expanded Disability Status Scale (EDSS) = 7.0 vs. b) switching until EDSS = 4.0, followed by escalation until EDSS = 7.0. The model analyzed social costs, quality-adjusted survival and effects of therapies in prolonging time without disability progression and burden of relapses. Clinical data were mainly extracted from a published observational study. RESULTS: Lifetime costs of early escalation to natalizumab and switching among immunomodulators amounted to €699,700 and €718,600 per patient, respectively. Early escalation was associated with prolonged quality-adjusted survival (11.19 vs. 9.67 QALYs, + 15.8%). A slight overall survival increase was also observed (20.10 vs. 19.67 life years). Both deterministic and probabilistic sensitivity analyses confirmed the robustness of findings. CONCLUSIONS: Adopting the Italian social perspective, early escalation to natalizumab is dominant vs. switching among immunomodulators, in RRMS patients who do not respond adequately to conventional immunomodulators.

The Impact of Price Reductions After Loss of Exclusivity in a Cost-Effectiveness Analysis: Fingolimod Versus Interferon Beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Cost-effectiveness analyses tend not to take into account the availability of lower-priced generics following loss of exclusivity (LOE) of branded products. By not considering these generics, which are typically adopted quickly, total costs are likely to be overestimated and may be unreflective of real-world payer conditions in the United States. OBJECTIVE: To assess the impact of including future price reductions following LOE on the cost-effectiveness of fingolimod versus intramuscularly administered interferon beta-1a (IM IFNß-1a) as treatments for multiple sclerosis. METHODS: This model was adopted from a previously published Markov model and was conducted from a U.S. payer perspective over a 10-year time horizon. Patients with relapsing-remitting multiple sclerosis entered the model and received either fingolimod (an oral therapy) or IM IFNß-1a (an injectable). These treatments reflect the interventions studied in the TRANSFORMS randomized clinical trial. Clinical, cost, and utility inputs were based on a recent cost-effectiveness review of therapies for multiple sclerosis. To model LOE, price reductions and the proportion of patients switching to generic versions following LOE were based on published estimates. Price reductions varied to reflect the difference in product types (oral vs. large molecule injectable). Assumptions were also made around the proportion of patients switching to generic versions over time following LOE and the projected date of LOE. Outcomes included per-patient total direct costs (medication, administration and monitoring, and disease-related costs including relapses), quality-adjusted life-years, and the incremental cost per quality-adjusted life-year. RESULTS: Assuming no price reductions following LOE, fingolimod was considered cost-effective versus IM IFNß-1a ($118,434 per quality-adjusted life-year), despite having higher total direct costs over 10 years ($475,740 vs. $446,792). When including future price reductions following LOE, total direct costs were reduced with fingolimod and were lower than those accrued with IM IFNß-1a over the model time horizon ($308,570 vs. $442,653). Cost-effectiveness results were sensitive to changes in both clinical parameters and medication costs. Scenario analyses demonstrated that an earlier date of LOE was associated with lower total costs. CONCLUSIONS: Health economic models may predict higher total costs when the price reductions following LOE are not considered. Here, oral fingolimod was seen to be cost-saving versus IM IFNß-1a over the model time horizon when such price reductions were included. The cost implications of not accounting for future price changes may determine whether an intervention is considered cost-effective and as such may influence reimbursement decisions based on cost-effectiveness thresholds. Multiple product types (e.g., oral, injectable, and infused agents) have been approved for use as treatments for multiple sclerosis in the United States, and LOE is likely to have a different effect on each of these therapies. DISCLOSURES: This study was funded by Novartis Pharmaceuticals Corporation. Hua and Hersh report consulting fees from Novartis for work on this study. Hua also reports speaking, advisory board, and consulting fees from Biogen, Genzyme, Teva, EMD Serono, Genentech, TG Therapeutics, and Novartis for activities outside of this study. Hersh also reports speaking and consulting fees from Novartis, Biogen, Genzyme, Genentech, and EMD Serono for activities outside of this study, and research grants from PCORI and Biogen. At the time of this research, Morten and Kusel were paid employees of Costello Medical, which was contracted by Novartis to undertake some of this study's work. Lin, Cave, Herrera, and Ko were paid employees of Novartis at the time of this research. Cave, Herrera, and Ko also report owning stock in Novartis Pharmaceuticals. Varga provided services to Novartis at the time of this research and has nothing further to disclose. This research was presented as a poster at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2017; March 27-30, 2017; Denver, CO.

Cost-Effectiveness of Alemtuzumab in the Treatment of Relapsing Forms of Multiple Sclerosis in the United States.

OBJECTIVE: To evaluate the cost-effectiveness of alemtuzumab compared with fingolimod, natalizumab, ocrelizumab, and generic glatiramer acetate 20 mg among patients with relapsing multiple sclerosis (RMS) in the United States. STUDY DESIGN: Markov model with annual periods from payer perspective. METHODS: The modeled population represented pooled patients from the CARE-MS I and II trials. Therapies' comparative efficacy at reducing relapses and slowing disability worsening was obtained from network meta-analyses. Safety information was extracted from package inserts. Withdrawal rates, treatment waning, resource use, cost, and utility inputs were derived from published studies and clinical expert opinion. To project the natural history of disease worsening, data from the British Columbia cohort was used. RESULTS: Alemtuzumab dominated comparators by accumulating higher total quality-adjusted life-years (QALYs) (8.977) and lower total costs ($421 996) compared with fingolimod (7.955; $1 085 814), natalizumab (8.456; $1 048 599), ocrelizumab (8.478; $908 365), and generic glatiramer acetate (7.845; $895 661) over a 20-year time horizon. Alemtuzumab's dominance was primarily driven by savings in treatment costs because alemtuzumab has long-term duration of response and is initially administered as 2 annual courses, with 36.1% of patients requiring retreatment over 5 years, whereas comparators are used chronically. In model scenarios where alemtuzumab's long-term duration of response was assumed not to hold and therapy had to be administered annually, probabilistic sensitivity analyses showed that alemtuzumab remained cost-effective versus ocrelizumab at a willingness-to-pay threshold of $100 000/QALY in 74% to 100% of model runs. CONCLUSIONS: Alemtuzumab was a cost-effective therapy. Model results should be used to optimize clinical and managed care decisions for effective RMS treatment.

Cost-effectiveness of Teriflunomide Compared to Interferon Beta-1b for Relapsing Multiple Sclerosis Patients in China.

BACKGROUND AND OBJECTIVE: Teriflunomide is a once-daily oral immunomodulatory agent approved in 80 countries for the treatment of patients with relapsing multiple sclerosis (RMS). The study objective was to estimate the cost effectiveness of teriflunomide (14 mg tablet, daily) versus interferon beta-1b (250 mcg subcutaneous injection, every other day) among RMS patients from the Chinese healthcare system perspective. METHODS: A Markov model with annual cycles and a lifetime horizon was utilized to assess cost-effectiveness of teriflunomide in comparison with interferon beta-1b in RMS patients. Treatment effects, including 3-month confirmed disability worsening and annualized relapse rate, were derived from a network meta-analysis. Cost inputs included costs related to treatment acquisition, administration, monitoring, natural disease management through Expanded Disability Status Scale states, relapse treatment, and adverse event management. These costs were calculated as the product between unit costs from published sources and healthcare resource utilization patterns identified in a survey conducted among 11 neurologists across different areas in China. Health effects were expressed as quality-adjusted life years (QALYs) with costs in local currency (¥) and US dollars (US$), 2018. RESULTS: Teriflunomide dominated interferon beta-1b and was associated with lower total costs (teriflunomide ¥1,887,144 vs interferon beta-1b ¥2,061,393) and higher QALYs (teriflunomide 9.60 QALYs vs interferon beta-1b 8.88 QALYs). In probabilistic sensitivity analysis, teriflunomide was dominant in 62.2% of model runs. CONCLUSION: Teriflunomide is a cost-effective therapy over a lifetime time horizon compared to interferon beta-1b in the treatment of RMS patients in China. Results should be interpreted with caution as head-to-head comparisons are not available.

Cladribine Tablets for the First-Line Treatment of Relapsing-Remitting Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group's review of the company's evidence submission for cladribine and the Appraisal Committee's final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group's main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company's cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company's economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources.

Value assessment of disease-modifying therapies for Relapsing-Remitting Multiple Sclerosis: HTA evidence from seven OECD countries.

This study systematically compares HTA recommendations on a number of disease-modifying therapies for patients with Relapsing-Remitting Multiple Sclerosis. We analysed publicly available HTA reports for nine medicine-indication pairs across seven OECD countries using a methodological framework enabling systematic analysis of HTA recommendations. The analysis was conducted based on a number of value dimensions, including clinical and economic variables, as well as several other dimensions of value beyond cost-effectiveness. The material was qualitatively and quantitatively coded following the different stages of HTA decision-making process. Fifty-seven medicine-indication pairs were assessed across the study countries. Of those, eight medicine indication-pairs reported diverging HTA recommendations. Although HTA recommendations were based on the same evidence submitted in most cases, significant variations were identified in interpretation and acceptance of evidence resulting in different uncertainties raised and different ways of addressing them. Uncertainties arose both in terms of the clinical and the economic evidence, including the design of key trials or the data quality in economic models. Beyond costs and effects, additional dimensions of value had an impact in the direction of recommendations, however with different magnitude across countries. We show that there is heterogeneity across countries in HTA for evaluating DMTs for RRMS with a lack of standardised methods in evaluating clinical and economic evidence and the use of social value judgments to inform decision-making.

Therapeutic Interferon Interchange in Relapsing Multiple Sclerosis Lowers Health Care and Pharmacy Expenditures with Comparable Safety.

INTRODUCTION: For patients with a less-active (fewer relapses or complete recovery from relapses, less radiologic burden of disease, or no or limited disease-related disability) relapsing form of multiple sclerosis (MS), interferon (IFN) beta-1b subcutaneous is similar in efficacy to IFN beta-1a intramuscular and subcutaneous. The purpose of this study was to assess the impact of patient interchange from an IFN beta-1a to IFN beta-1b. METHODS: This was a retrospective, pre-post study of adult patients with relapsing MS who underwent interchange from an IFN beta-1a to IFN beta-1b between April 15, 2014, and April 30, 2015. Health care financial and utilization outcomes between the 6 months before and after interchange were compared, and safety outcomes after interchange were assessed. RESULTS: A total of 36 primarily white, middle-age, and female patients underwent interchange. Monthly total health care and pharmacy expenditures decreased by approximately 40% and 44%, respectively, from pre-to-post interchange (p < 0.001). Health care utilization was unchanged (p < 0.05). Seven (43.8%) patients underwent interchange back to IFN beta-1a intramuscular. No patients underwent interchange back to IFN beta-1a subcutaneous. The most common adverse effect reported after interchange was injection-site reaction. CONCLUSION: Health care expenditures decreased and adverse effects were limited among patients with MS who underwent an interchange from an IFN beta-1a to IFN beta-1b. These findings suggest that a therapeutic interchange between IFNs for patients with less-active MS disease is well tolerated. Further research is needed to determine the impact of such an interchange on disease progression.

Disease-Modifying Therapies for Relapsing-Remitting and Primary Progressive Multiple Sclerosis: A Cost-Utility Analysis.

BACKGROUND: Several disease-modifying therapies (DMTs) treat relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Few comprehensive cost-effectiveness analyses exist in this area, particularly from a payer perspective, despite rapidly increasing prices of DMTs. OBJECTIVE: We aimed to systematically compare cost effectiveness of all relevant DMTs for first-line treatment of RRMS, second-line treatment of RRMS, and first-line treatment of PPMS. METHODS: We used a Markov model with health states based on Expanded Disability Status Score categories. Upon discontinuing first-line treatment, RRMS patients continued to second-line therapy then to supportive care, and PPMS patients moved directly to supportive care. Data was sourced from clinical trials and commercially and publicly available sources. The target population was treatment-naïve adults with RRMS or PPMS. We used a lifetime horizon from a US payer perspective, and compared DMTs for RRMS (first-line: dimethyl fumarate, glatiramer acetate, interferon ß-1a, interferon ß-1b, peginterferon ß-1a, teriflunomide, natalizumab, fingolimod, and ocrelizumab; second-line: alemtuzumab, natalizumab, fingolimod, and ocrelizumab), ocrelizumab for PPMS, and supportive care. Outcome measures included total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: For RRMS first-line therapy, ocrelizumab dominated the other DMTs with an ICER of US$166,338/QALY compared with supportive care. For RRMS second-line therapy, alemtuzumab dominated the other three DMTs, providing more QALYs for lower costs. For PPMS, ocrelizumab had an ICER of US$648,799/QALY compared with supportive care. Wide variability in results was observed in the probabilistic sensitivity analysis. Results were sensitive to the relative risk of progression and cost of DMTs. CONCLUSIONS: Ocrelizumab would likely be cost effective as a first-line treatment for RRMS with a discounted price but was not cost effective for PPMS. Alemtuzumab dominated other options for second-line treatment of RRMS. Other DMTs were generally similar in terms of costs and health outcomes, providing health benefits compared to supportive care but with significant added costs. If drug prices were lowered, more DMTs could be cost effective.

Modeling Approaches in Cost-Effectiveness Analysis of Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: An Updated Systematic Review and Recommendations for Future Economic Evaluations.

BACKGROUND: Numerous cost-effectiveness analyses (CEAs) of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have been published in the last three decades. Literature reviews of the modeling methods and results from these CEAs have also been published. The last literature review that focused on modeling methods, without country or time horizon in the inclusion criteria, included studies published up to 2012. Since then, new DMTs have become available, and new models and data sources have been used to assess their cost effectiveness. OBJECTIVE: The aim of this systematic review was to provide a detailed and comprehensive description of the relevant aspects of economic models used in CEAs of DMTs for RRMS, to understand how these models have progressed from recommendations provided in past reviews, what new approaches have been developed, what issues remain, and how they could be addressed. METHODS: EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), the National Health System (NHS) Economic Evaluations Database, the Health Technology Assessment (HTA) Database, and EconLit were searched for cost-effectiveness studies of DMTs for RRMS that used decision-analytic models, published in English between 1 January 2012 and 24 December 2017. The inclusion criteria were as follows: being a full economic evaluation, a decision-analytic model was used, the target population concerned adult patients with RRMS, and being available in full-text format. Studies were not excluded based on the methodological quality. The background information of the included studies, as well as specific information on the components of the economic models related to the areas of recommendation from previous reviews were extracted. RESULTS: Twenty-three studies from ten countries were included. The model structure of these studies has converged over time, characterizing the course of disease progression in terms of changes in disability and the occurrence of relapses over time. Variations were found in model approach; data sources for the natural course of the disease and comparative efficacy between DMTs; number of lines of treatment modeled; long-term efficacy waning and treatment discontinuation assumptions; type of withdrawal; and criteria for selecting adverse events. Main areas for improvement include using long-term time horizons and societal perspective; reporting relevant health outcomes; conducting scenario analyses using different sources of natural history and utility values; and reporting how the model was validated. CONCLUSION: The structure of economic models used in CEAs of DMTs for RRMS has converged over time. However, variation remains in terms of model approach, inputs, and assumptions. Though some recommendations from previous reviews have been incorporated in later models, areas for improvement remain.

Cost-effectiveness of cladribine tablets, alemtuzumab, and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England.

AIMS: Cladribine tablets were the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA-RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA-RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England. MATERIALS AND METHODS: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale [EDSS] plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. The treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modeled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses. RESULTS: Cladribine tablets were dominant (i.e., less costly and more effective) vs alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC. LIMITATIONS: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken. CONCLUSIONS: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England.