Cost-effectiveness of cladribine tablets and dimethyl fumarate in the treatment of relapsing remitting multiple sclerosis in Spain.

Aim: To analyze the cost-effectiveness of treatment of relapsing remitting multiple sclerosis (RRMS) with cladribine tablets (CladT) and dimethyl fumarate (DMF) from the perspective of the Spanish National Health System (NHS). Methods: A probabilistic Markov model (second-order Monte Carlo simulation) with a 10-year time horizon and annual Markov cycles was performed. Results: CladT was the dominant treatment, with lower costs (-74,741 € [95% CI: -67,247; -85,661 €]) and greater effectiveness (0.1920 [95% CI: -0.1659; 0.2173] QALY) per patient, compared with DMF. CladT had a 95.1% probability of being cost-effective and a 94.1% chance of being dominant compared with DMF. Conclusion: CladT is the dominant treatment (lower costs, with more QALYs) compared with DMF in the treatment of RRMS in Spain.

Economic evaluation of cladribine tablets in high disease activity (HDA) relapsing multiple sclerosis (RMS) patients in Lebanon.

BACKGROUND: Cladribine tablets are a newly launched short course oral treatment approved for high disease activity (HDA) relapsing multiple sclerosis (RMS). The current analysis assessed the cost-utility and budgetary impact of introducing cladribine tablets in HDA-RMS patients compared with other HDA-RMS therapies in Lebanon. METHODS: The global cost-utility and budget impact models were adapted from Lebanese National Social Security Fund (NSSF) perspective. The data for the models' adaptation were retrieved from the literature and validated by Lebanese experts. The comparators considered in the cost-utility model were alemtuzumab, fingolimod, and natalizumab while budget impact analysis additionally considered dimethyl fumarate. A sensitivity analysis was also performed to assess the uncertainty in the analysis. RESULTS: The cost-utility results showed that cladribine tablets are an economically dominant therapeutic strategy (i.e., less costly and better quality-adjusted life year [QALY]) compared to all comparators. The cost saving was driven by drug acquisition, administration, and monitoring costs; while incremental QALY gain was driven by differences in delayed Expanded Disability Status Scale progression. Sensitivity analysis showed that cladribine tablets have a high probability (99.3-100%) of being dominant at a threshold of 22,000 United States Dollars (approximately three times of gross domestic product) per QALY gained against different comparators. The budget impact analysis showed that the introduction of cladribine tablets would result in 5.0% to 21.5% savings in the overall budget over a period of five years. CONCLUSIONS: Cladribine tablets are a cost-effective and a budget-saving treatment option for the treatment of HDA-RMS patients in Lebanon from the NSSF perspective.

[Pharmacoeconomic aspects of using cladribine (in tablets) for treatment of adult patients with remitting multiple sclerosis]. / Farmakoekonomicheskie aspekty primeneniya kladribina dlya lecheniya vzroslykh patsientov s vysokoaktivnym remittiruyushchim rasseyannym sklerozom.

OBJECTIVE: To conduct a pharmacoeconomic analysis of using cladribine (in tablets) as a second-line treatment option for adult patients with highly active remitting multiple sclerosis in Russia. MATERIAL AND METHODS: Current treatment practice of highly active multiple sclerosis (natalizumab, fingolimod, alemtuzumab, ocrelizumab) was considered as a comparator for cladribine (in tablets). Clinical and economic study was conducted using the «cost minimization¼ method. For budget impact analysis cost of using cladribine (in tablets) was compared to the cost of using current treatment practice. RESULTS: Cladribine in tablets is a cost-saving alternative for treatment of patients with highly active multiple sclerosis compared to the current treatment practice. Within a 4-year period direct medical costs reduction is 2 million RUB (50.1%) per person. CONCLUSION: In case of switching the patients, who are currently provided with other disease modifying drugs, to cladribine, in 4 years health budget will save up to 6284 million RUB (50.1%).

Economic Evaluation of Cladribine Tablets in Patients With High Disease Activity-Relapsing-Remitting Multiple Sclerosis in the Kingdom of Saudi Arabia.

OBJECTIVE: Cladribine tablets are the first short-course oral treatment approved for high disease activity relapsing-remitting multiple sclerosis (HDA-RRMS) across various countries. This analysis assessed the cost-effectiveness of introducing cladribine tablets as a treatment option for patients with high disease activity compared with other HDA-RRMS therapies in the Kingdom of Saudi Arabia (KSA). METHODS: The cost-effectiveness model was adapted from the KSA payer's perspective. Data for the model's adaptation were retrieved from the literature and validated by key opinion leaders. The comparators considered in the model were alemtuzumab, dimethyl fumarate, fingolimod, interferon beta-1a (subcutaneous and intramuscular) and beta-1b, natalizumab, and teriflunomide. A sensitivity analysis was also performed to assess the robustness of the analysis. RESULTS: The cost-effectiveness results showed cladribine tablets as the dominant strategy (ie, less costly and more effective) versus all the comparators. The incremental cost and quality-adjusted life-years gained were largely driven by drug acquisition cost and delayed expanded disability status scale progression, respectively. Cladribine tablets showed an 81% to 100% probability of being cost-effective at a threshold of Saudi Riyal 225 326 per quality-adjusted life-years gained against different comparators. CONCLUSIONS: Cladribine tablets are a dominant treatment option for patients with HDA-RRMS from the payer perspective in the KSA.

Cladribine tablets are a cost-effective strategy in high-disease activity relapsing multiple sclerosis patients in Iran.

Background: Cladribine tablets are the foremost oral immune-reconstitution therapy for high disease activity relapsing multiple sclerosis (HDA-RMS). We aimed to assess the cost-effectiveness of cladribine tablets compared to natalizumab in patients with HDA-RMS in Iran. Methods: A 5-year cohort-based Markov model was developed with 11 expanded disability status score (EDSS) health states, including patients with HDA-RMS as on and off-treatment. All costs were identified from the literature and expert opinion and were measured in Iranian Rial rates, changed to the 2020 USD rate and were discounted by 7.2%. Quality adjusted life years (QALY), discounted by 3.5%, and life years gained (LYG) were adopted to measure efficacy. The final results were presented as incremental cost-effectiveness ratio that was compared to a national willingness to pay (WTP) threshold of 1 to 3 gross domestic product (GDP) per capita. Deterministic and probabilistic sensitivity analyses (D/PSA) were employed to evaluate uncertainty. Results: Cladribine tablets dominated natalizumab and yielded 6,607 USD cost-saving and 0.003 additional QALYs per patient. LYG was comparable. The main cost component was drug acquisition cost in both arms. DSA indicated the sensitivity of the results to the cost discount rates and also the patients' body weight; while they were less sensitive to the main clinical variables. PSA indicated that cladribine tablets were cost-effective in Iran, with a probability of 57.5% and 58.6% at lower and higher limits of threshold, respectively. Conclusion: Cladribine tablets yielded higher QALYs and lower costs compared to natalizumab, in patients with HDA-RMS in Iran.

Cladribina oral para o tratamento da esclerose múltipla remitente-recorrente altamente ativa: análise de impacto orçamentário sob a perspectiva do sistema brasileiro de saúde suplementar / Cladribine tablets for the treatment of highly active recurrent multiple sclerosis: budget impact analysis from the perspective of the Brazilian supplementary health system

Objetivo: Avaliar o impacto orçamentário da inclusão da cladribina oral no tratamento de esclerose múltipla remitente-recorrente em alta atividade da doença (EMRR HDA) no Sistema de Saúde Suplementar (SSS). Métodos: Foi conduzida uma análise de impacto orçamentário, sob a perspectiva do SSS, com horizonte temporal de quatro anos, considerando a abordagem de coorte aberta na qual o número de pacientes elegíveis para tratamento varia em cada ano com a introdução de novos pacientes diagnosticados de EMRR HDA e a retirada de indivíduos prevalentes devido a morte ou progressão secundária. Foram considerados custos médicos diretos, incluindo a aquisição e administração de medicamentos, monitoramento, eventos adversos e surtos. Os comparadores utilizados na análise foram: alentuzumabe, fingolimode, natalizumabe e ocrelizumabe. Os custos foram apresentados em real brasileiro (BRL). Resultados: O custo incremental da inclusão da cladribina oral para o SSS foi estimado em 463.265 BRL, 739.691 BRL, -1.414.963 BRL, -3.719.007 BRL, nos anos 1, 2, 3 e 4, respectivamente. Isso resultou em um custo incremental total de -3.931.015 BRL no período analisado, representando 1,5% da redução orçamentária total no tratamento de EMRR HDA. Conclusão: A inclusão da cladribina oral para o tratamento de pacientes com diagnóstico de EMRR HDA poderia gerar uma economia substancial para o sistema brasileiro de saúde suplementar, atingindo um valor de cerca de 3,9 milhões de BRL em um período de quatro anos

Objective: To evaluate the budget impact of adopting cladribine tablets as a treatment strategy for relapsing remitting multiple sclerosis with high disease activity (RRMS HDA), from the Brazilian private healthcare system perspective. Methods: A budget impact analysis, under private healthcare system perspective, with a 4-years time horizon was conducted, considering the open cohort approach in which the number of patients eligible for treatment varies each year with the introduction of newly diagnosed RRMS HDA patients and the drop out of prevalent individuals due to death or secondary progression. Direct medical costs, including acquisition, drug administration, monitoring, adverse events and relapses were considered. Comparators used in the analysis were: alentuzumab, fingolimod, natalizumab and ocrelizumab. Costs were presented in Brazilian real (BRL). Results: The incremental cost of incorporating cladribine tablets into the private healthcare system was estimated at 463,265BRL, 739,961BRL, -1,414,963 BRL, -3,716,007 BRL, in years 1, 2, 3 and 4, respectively. This resulted in a total incremental cost of -3,931,015 BRL over the period analyzed, representing 1.5% of the total budget reduction in the treatment of RRMS HDA. Conclusion: Incorporation of cladribine tablets for the management of RRMS HDA could generate substantial savings for the private healthcare system, reaching a value of approximately 3.9 million BRL in a 4-years period

Cost-effectiveness of cladribine tablets versus fingolimod in patients with highly active relapsing multiple sclerosis in Portugal.

Aims: To assess the cost-utility of cladribine tablets versus fingolimod in patients with highly active relapsing-remitting multiple sclerosis (RRMS) in Portugal.Methods: A 1-year cycle cohort-based Markov state transition model was developed to simulate disease progression, measured by Kurtzke Expanded Disability Status Scale (EDSS), relapses, and conversion to secondary-progressive MS (SPMS). Patients were assumed to remain on treatment until progression to EDSS level 7, conversion to SPMS, or complete loss of efficacy due to waning effect. Natural history was based on British Columbia Multiple Sclerosis registry, London Ontario database, UK MS Trust, and cladribine tablets clinical trial (CLARITY). Portuguese all-cause mortality was adjusted for the MS associated increased mortality. Clinical inputs for active treatments (disability progression and relapse rate) were estimated on a network meta-analysis. Utility weights were derived from UK-MS Survey and published literature. Resource consumption by EDSS and due to relapses was based on published literature, National DRG microdata and expert opinion. Unit costs were obtained from official sources. The analysis was conducted from payers' perspective, time horizon of 50 years and discount rate of 5%, for both costs and benefits. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses.Results: Compared to fingolimod, cladribine tablets were associated with a delay in progression, resulting in a gain of 0.85 quality adjusted life years (QALYs) and a cost decrease of 25,935 €. Probabilistic sensitivity analysis resulted in a mean ICER of -31,781 € per QALY and was dominant in 98.7% of the simulations. Cladribine tablets were dominant across the scenario analyses tested.Conclusions: Treatment of highly active RRMS with cladribine tablets was less costly and more effective than treatment with fingolimod. Hence, it is a dominant strategy in the Portuguese setting. No conclusions can be drawn from the present study regarding other treatment options, in particular natalizumab and alemtuzumab.

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.

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.

Benefit-risk Assessment of Cladribine Using Multi-criteria Decision Analysis (MCDA) for Patients With Relapsing-remitting Multiple Sclerosis.

PURPOSE: We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit-risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model that incorporated available evidence on DMDs for RRMS and clinical judgments about the relevance of the evidence. Benefit-risk assessments were conducted for DMDs in both patients with RRMS and patients with RRMS with high disease activity (HDA; defined as ≥2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit-risk calculation. The neurologists weighted different efficacy and safety profile attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs. FINDINGS: The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76), followed by alemtuzumab (62) and natalizumab (61). The benefit-risk balance of cladribine in patients with RRMS and specifically patients with RRMS who exhibited HDA characterized by high relapse activity (≥2 relapses in the previous year) was more favorable than the other DMDs included in the model. IMPLICATIONS: The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and patients with HDA. Regular, single-country meetings could be organized to explore how differences in cultural values (scores and weights) and updated input data might affect the usefulness of MCDA in different, real-world, dynamic clinical settings.

Treating the ineligible: Disease modification in people with multiple sclerosis beyond NHS England commissioning policies.

BACKGROUND: Whilst there is a broad selection of drugs licensed as disease modifying treatments (DMTs) for people with relapsing multiple sclerosis (pwRMS), access to DMTs remains restricted, particularly for people with progressive MS (pwPMS). Cladribine has shown efficacy at all stages of MS. Following withdrawal from the market of oral cladribine in 2011, partly due to issues associated with lymphopenia, and following a thorough risk assessment, we started using subcutaneously injected cladribine (Litak®) to treat both pwRMS and pwPMS. Here, we report on the real life safety and tolerability of this treatment option. METHODS: Cladribine was offered to (i) pwRMS as a choice despite fulfilling NHS England (NHSE) criteria for licensed DMTs, and (ii) pwRMS and pwPMS not eligible for NHSE approved DMTs. To avoid lymphocyte depletion lower than 0.5 × 109/l (WHO grade 2) cladribine was administered using a personalised dosing scheme (30-40 mg in week 1; and another 0-30 mg in week 5 pending total lymphocyte count at week 4). Anti-viral prophylaxis was given from day 1 for 60 days. Patients approaching week 48 were given a second treatment cycle. Data collection included side effects, relapses, change in disability and MRI indices. RESULTS: Seventy-one pwMS (40 female, 31 male; 36 RMS, 35 PMS,) received at least one treatment cycle. Mean age for starting cladribine was 44 years (range 22-72 years), median EDSS was 5 (range 1-8.5). Maximum follow-up was 28 months. 35/71 pwMS were followed up for at least 20 weeks. These patients had a median EDSS of 5.0 (range 1.0-7.5) at baseline and 5.5 (range 1.0-8.0) after a mean follow-up of 11 months (range 5-28). Cladribine was well tolerated with very few treatment-related adverse events observed. Personalised dosing led to grade 1-2 lymphopenia in 50% of cases. A single patient developed transient grade 3 lymphopenia. No cases of varicella or other infections were observed. Four/17 people with relapsing MS, experienced a total of six relapses during a mean follow-up of 13 months (range 5-28 months). In people with PMS (n = 18) median EDSS was 5.5 (2.0-7.5) at baseline and 6.0 (2.5-7.5) after a median of 10 months (range 5-18). In pwPMS MRI showed that 25% had active scans at baseline, and 0% at follow-up. CONCLUSION: Personalised dosing of cladribine avoided severe lymphopenia in all but one patients and was very well tolerated across a large spectrum of disease severity. Our data suggests cladribine may offer benefit people with relapsing and progressive MS alike. The personalised protocol used appears safe, however warrants controlled studies to more definitively assess efficacy and safety, particularly in groups of pwMS who are not eligible for licensed DMT including oral cladribine (Mavenclad®).

Cladribine: Off-label disease modification for people with multiple sclerosis in resource-poor settings?

BACKGROUND: A considerable number of people with multiple sclerosis (pwMS) live in low- and middle-income countries (LMIC), where lack of resource adversely affects access to effective disease-modifying treatment. OBJECTIVE: The objective of this commentary is to propose a useful cost-effective disease-modifying treatment option for pwMS in LMIC with potential high efficacy and high convenience to the pwMS and treating physician.Viewpoint: We propose using generic 2-chloro-2'-deoxyadenosine (cladribine), a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II and III trials to be a highly effective disease-modifying treatment for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high-income economies where an oral preparation has recently been licensed by the European Medicines Agency. CONCLUSION: Our viewpoint takes into account experience we have gathered over the past three years in the use of generic cladribine to treat pwMS. Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.

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.