Cost, efficacy, and safety comparison between early intensive and escalating strategies for multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: The optimal treatment strategy of multiple sclerosis (MS) is a matter of debate. The classical approach is the escalating (ESC) strategy, which consists of starting with low- to moderate-efficacy disease-modifying drugs (DMDs) and upscale to high-efficacy DMDs when noting some evidence of active disease. Another approach, the early intensive (EIT) strategy, is starting with high-efficiency DMDs as first-line therapy. Our goal was to compare effectiveness, safety, and cost of ESC and EIT strategies. METHODS: We searched MEDLINE, EMBASE and SCOPUS until September 2022, for studies comparing EIT and ESC strategies in adult participants with relapsing-remitting MS and a minimum follow-up of 5 years. We examined the Expanded Disability Severity Scale (EDSS), the proportion of severe adverse events, and cost in a 5-year period. Random-effects meta-analysis summarized the efficacy and safety and an EDSS-based Markov model estimated the cost. RESULTS: Seven studies with 3,467 participants showed a 30% reduction in EDSS worsening in 5 years (RR 0.7; [0.59-0.83]; p < 0.001) in the EIT group vs in the ESC group. Two studies with 1,118 participants suggested a similar safety profile for these strategies (RR 1.92; [0.38-9.72]; p = 0.4324). EIT with natalizumab in extended interval dosing, rituximab, alemtuzumab, and cladribine demonstrated cost-effectiveness in our model. DISCUSSION: EIT presents higher efficacy in preventing disability progression, a similar safety profile, and can be cost-effective within a 5-year timeline.

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.

Cladribina oral para tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa, conforme protocolo do Ministério da Saúde / Oral cladribine for the treatment of patients with highly active relapsing-remitting multiple sclerosis, according to the Ministry of Health protocol

CONTEXTO: A esclerose múltipla é uma doença inflamatória crônica, que afeta o SNC, com quadro clínico incapacitante, como fadiga intensa, fraqueza muscular, alteração do equilíbrio da coordenação motora, disfunção intestinal e da bexiga, e que tem como consequência uma queda na qualidade de vida dos pacientes. Dentre as formas dessa doença há a esclerose múltipla remitente recorrente altamente ativa (EMRRaa). No Sistema Único de Saúde (SUS), os pacientes com EMRRaa possuem como 1ª linha de tratamento, o natalizumabe, que tem contraindicações para alguns pacientes. Assim, cladribina oral, apresenta-se como uma alternativa terapêutica para os pacientes com EMRRaa, com uma posologia facilitada na perspectiva do paciente e do sistema de saúde, uma vez que é um medicamento de administração oral com até 20 dias de tratamento nos dois primeiros anos, e com a menor carga de monitoramento durante o tratamento. PERGUNTA: Cladribina oral é eficaz, seguro e custo-efetivo para o tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa quando comparado ao natalizumabe? EVIDÊNCIAS CIENTÍFICAS: As evidências clínicas da comparação entre a cladribina versus o natalizumabe foram apresentadas através de uma revisão sistemática com metanálise de comparação indireta, que utilizou o ensaio clínico pivot

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.

Cladribina en esclerosis múltiple remitente recidivante de alta actividad / Cladribine in remitting multiple sclerosis high activity relapsing

La esclerosis múltiple (EM) es una enfermedad inflamatoria inmunomediada, desmielinizante y neurodegenerativa del sistema nervioso central. Es una de las principales causas de discapacidad en los adultos jóvenes. La enfermedad generalmente se presenta alrededor de los 30 años y las tasas de prevalencia alcanzan su punto máximo alrededor de los 50 años. La etiología de la EM no se encuentra del todo establecida. Se identifican distintas formas clínicas de acuerdo al modo de presentación y curso de la enfermedad, siendo la más frecuente la denominada Esclerosis Múltiple Recurrente Recidivante (EMRR). El curso más frecuente de la EMRR se caracteriza por recaídas y remisiones de síntomas neurológicos asociados a áreas de inflamación del SNC con recuperación total o parcial entre los brotes y acumulación gradual de discapacidad. Al cabo de dos décadas, más de la mitad de los pacientes no tratados entran en una fase con empeoramiento sostenido de la discapacidad independientemente de las recaídas, conocido como EM secundaria progressiva. La enfermedad presenta gran variabilidad en cuanto a su evolución clínica, severidad de las recaídas, así como en la progresión y gravedad de la discapacidad. Esto genera un impacto negativo sobre la calidad de vida de los pacientes tanto por la enfermedad como por los efectos adversos y la carga de los tratamientos, así como sobre la capacidad laboral y la afección al entorno familiar. El diagnóstico se realiza mediante un conjunto de criterios clínicos y de imágenes (conocidos como criterios de Mc Donalds, última versión 2017). El nivel de discapacidad generalmente es valorado con un instrumento específico conocido como escala ampliada del estado de discapacidad (EDSS), que consiste en una escala ordinal que va de 0 (estado clínico normal) a 10 (muerte por EM) midiendo cambios mediante incrementos de 0,5 a 1 puntos, iniciando en 0.3 Dicha escala tiene en cuenta distintas esferas del examen neurológico (funciones motoras, sensoriales, cerebelosas, tronco encefálico, visuales, intestinales y de vejiga, piramidales y otras funciones). OBJETIVO: El objetivo del presente informe es evaluar la eficacia, seguridad, recomendaciones, políticas de cobertura y aspectos económicos del tratamiento con cladribina oral en pacientes con EMRR-AA. METODOLOGÍA: Se realizó la búsqueda de evidencia en los sitios públicos de Pubmed, LILACS, BRISA/REDETSA-, CRD (del inglés, Centre for Reviews and Dissemination- University of York), Cochrane; Epistemónikos, el registro Clinicaltrials.gov, GIN (Guidelines International Network) en "buscadores genéricos de internet", sociedades científicas, sitios web de distintos organismos gubernamentales responsables de definir cobertura de medicamentos. En lo que respecta a ETS, la búsqueda incluyó: la Base de datos internacional para las ETS de INHATA (su sigla del inglés, International Network of Agencies for Health Technology Assessment), EUneHTA (European Network for Health Technology Assessment) Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y en agencias tales como NICE (del inglés, National Institute for Health and Clinical Excellence) del Reino Unido; PBAC (del inglés, The Pharmaceutical Benefits Advisory Committee) de Australia; CADTH (del inglés, Canadian Agency for Drugs and Technologies in Health) de Canadá y CONITEC (del portugués, Comissão Nacional de Incorporação de Tecnologías no SUS) de Brasil. Se utilizó en pubmed la siguiente estrategia: (cladribine [MeSH] OR cladribine[tiab] OR mavenclad[tiab] OR disease modifying[tiab]) AND ("Multiple Sclerosis, RelapsingRemitting"[Mesh] OR "Multiple Sclerosis"[Mesh] OR multiple sclerosis, relapsingremitting[tiab] OR remitting-relapsing multiple sclerosis[tiab] OR multiple sclerosis, acute relapsing[tiab] OR acute relapsing multiple sclerosis[tiab]). Utilizando filtros de diseños: ensayos clínicos, revisiones sistemáticas y metaanálisis y temporales (2010-2021). RESULTADOS: Se presentan los resultados globales de la búsqueda bibliográfica y el flujograma que muestra las distintas instancias de valoración de los artículos identificados, de acuerdo a los criterios de inclusión y exclusión definidos a través de los componentes de la pregunta PICO, concluyendo con el número de artículos seleccionados para el contenido del presente informe. CONCLUSIONES: La EMRR constituye una enfermedad neurológica con curso clínico y pronóstico muy variable; si bien hay acuerdo en la existencia de grupos que pueden considerarse como con Alta Actividad de la enfermedad, no hay consenso internacional sobre su definición concreta, lo que dificulta estimar tanto su frecuencia como comparar el impacto de los tratamientos sobre su evolución en los distintos estudios que valoran diferentes fármacos y estrategias terapéuticas. Existe evidencia directa que reporta beneficio de cladribina con respecto a placebo en cuanto a la reducción en la TRA (Alta certeza) y progresión de la discapacidad confirmada por 6 meses (Moderada certeza) en pacientes con EMRR. El impacto sobre la progresión de la discapacidad por 6 meses podría ser superior en la población de Alta Actividad (Baja certeza). Con respecto al impacto en la calidad de vida, el mismo es incierto, debido a que la información para su evaluación mediante la herramienta específica para la enfermedad fue escasa, con pequeño número de pacientes evaluados para este desenlace (Muy Baja certeza) aunque podría generar mejoría cuando se midió con escalas generales (Baja certeza). La evidencia sobre la eficacia y seguridad comparativas de cladribina con respecto a las otras DME utilizadas generalmente en el tratamiento de esta subpoblación (Alta Actividad) proviene de comparaciones indirectas dada la falta de estudios que evalúen distintas DME cabeza a cabeza. Los MAR incluidos en el presente informe no reportan diferencias significativas de cladribina con respecto a los comparadores. Es importante considerar que la evidencia es insuficiente, las estimaciones resultan imprecisas y la heterogeneidad en distintas características de las poblaciones incluidas en los estudios, particularmente para el subgrupo de Alta Actividad, dificultan la interpretación de los resultados. No fue posible realizar una valoración formal de la certeza de la evidencia indirecta (MAR) mediante la metodología GRADE por no contar con la información necesaria; sin embargo, los hallazgos reportados (falta de diferencias significativas) fueron consistentes entre las dos RS. Las guías de práctica clínica y recomendaciones internacionales en su mayoría sugieren el uso de cladribina en EMRR-AA ya sea como primera línea de tratamiento en pacientes con enfermedad severa progresiva, como en segunda línea en aquellos que no presentan respuesta adecuada al tratamiento con otras DME. Enfatizan la necesidad de la selección del fármaco de acuerdo a las características individuales de los pacientes (actividad y severidad de la enfermedad, comorbilidades, etc). Respecto a políticas de cobertura, la mayoría de los países de altos ingresos recomienda el uso de cladribina cuando existe inadecuada respuesta o intolerancia a otro tratamiento previo para EMRR, o enfermedad severa, rápidamente progresiva, en algunos casos requiriendo reducción de costos. En Latinoamérica, Chile recomienda su cobertura bajo condiciones específicas (fallo documentado del tratamiento con otras DME o intolerancia o efectos adversos graves con otros tratamientos). participación de mercado de alemtuzumab, ocrelizumab, natalizumab y fingolimod. Cuando se evalúa el impacto presupuestario utilizando los precios a los que ha comprado los fármacos una obra social provincial deja de ser costo ahorrativo sólo cuando se analiza el desplazamiento del 100% de fingolimod, pero se demuestra costo ahorrativo frente al resto de los comparadores.

Cladribina oral no tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa / Oral cladribine in the treatment of patients with highly relapsing-remitting multiple sclerosis active

INTRODUÇÃO: A esclerose múltipla é uma doença inflamatória crônica, que afeta o SNC, com quadro clínico incapacitante, como fadiga intensa, fraqueza muscular, alteração do equilíbrio da coordenação motora, disfunção intestinal e da bexiga, e que tem como consequência uma queda na qualidade de vida dos pacientes. Dentre as formas dessa doença há a EMRR altamente ativa, que possui uma janela de tratamento entre o primeiro evento desmielinizante e a progressão. No Sistema Único de Saúde (SUS), os pacientes com EMRR altamente ativa possuem como opções terapêuticas o Natalizumabe, de administração intravenosa e, que gera dificuldade operacionais relacionados a infusão, maior necessidade de um monitoramento dos pacientes, e alguns efeitos adversos graves. Assim, cladribina oral, apresenta-se como uma alternativa terapêutica para os pacientes com EMRR altamente ativa no SUS, com uma posologia facilitada na perspectiva do paciente e do sistema de saúde, uma vez que é um medicamento de administração oral com até 20 dias de tratamento nos dois primeiros anos, e com a menor carga de monitoramento e de custo operacional entre os tratamentos. TECNOLOGIA: Cladribina oral (Mavenclad®). PERGUNTA: Cladribina oral é eficaz, seguro e custo-efetivo para o tratamento de pacientes com esclerose múltipla remitente-recorrente altamente ativa quando comparado ao natalizumabe? EVIDÊNCIAS CLÍNICAS: As evidências clínicas da comparação entre a cladribina versus o natalizumabe foi apresentada através de uma revisão sistamática com meta-análise em rede, que utilizou o ensaio clínico pivot de cada tecnologia para a metanálise em rede, e assim foi classificada como de baixa qualidade por ser uma comparação indireta realizada com população não específica deste dossiê. Apoiado nesta evidência foi assumido que as tecnologias são similares, pois não apresentaram diferença estatisticamente significante nos diversos desfechos analisados. AVALIAÇÃO ECONÔMICA: Uma análise de custo-minimização foi realizada comparando o custo do tratamento, composto do custo de aquisição da medicação + administração + monitoramento + manejo dos eventos adversos. No entanto, os dados apresentados não estão de acordo com a posologia apresentada e o valor proposto para incorporação. Apesar do custo incremental de R$ 13.788,24 por paciente, ele está claramente subestimado. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário utilizou metodologia recomendada pelas diretrizes do Ministério da Saúde, utilizando demanda aferida com pesquisa no DATASUS, além de alguns dados de projeção de números do próprio demandante de market-share, no entanto, foi realizado uma análise de sensibilidade. A inconsistência dos custos apresentadas na análise de custo-minimização enviesa toda análise de impacto orçamentária e deve ser revista pelo demandante. EXPERIÊNCIAS INTERNACIONAIS: O Reino Unido, a Austrália, o Canadá, a Escócia e a Irlanda incorporaram a cladribina para o tratamento da EMRR. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Não há tecnologias identificadas no horizonte temporal para EMRR altamente ativa. PERSPECTIVA DO PACIENTE: A chamada pública de número 51/2021 para participar da Perspectiva do Paciente sobre o tema foi aberta de 13/09/2021 a 27/09/2021 e quarenta e duas pessoas se inscreveram. A indicação dos representantes titular e suplente para fazer o relato da experiência foi feita a partir a partir de sorteio realizado em plataforma digital com transmissão em tempo real acessível a todos os inscritos. No relato, a participante descreveu como o uso do medicamento em avaliação teve bons resultados no seu caso, destacando a comodidade do uso e a ausência de efeitos adversos. CONSIDERAÇÕES FINAIS: As evidências ainda demonstram incerteza na similaridade da cladribina em relação ao natalizumabe, não há um escopo de evidências mais robusta, pois não há estudos de comparação direta, e que envolva a população alvo específica. Desta forma, coloca a análise de custo-minimização em uma posição de risco em assumir a não diferença entre as tecnologias analisadas. Além disso, a análise de custo-minimização apresentada contém inconsistência, com possível valores subestimados, e deve ser revista para que os valores projetados fiquem o mais próximo dos dados de vida real. Desta forma, a cladribina, se mostra uma tecnologia dominada pelo natalizumabe, com a ressalva de sua administração via oral que traz comodidade ao portador de EMRR altamente ativa e o impedimento do uso nos casos de risco no desenvolvimento de LEMP. RECOMENDAÇÃO PRELIMINAR: o Plenário da Conitec, em sua 106ª Reunião Ordinária, no dia 09 de março de 2022, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar desfavorável à incorporação, da cladribina oral para o tratamento de primeira linha da esclerose múltipla remitente-recorrente de pacientes com alta atividade da doença com opção de tratamento de natalizumabe no SUS. Os membros da Conitec consideraram que a evidência científica ainda é inconsistente, que há problemas na análise econômica e que mesmo subestimada é uma tecnologia dominada, dada a opção de uso do natalizumabe. CONSULTA PÚBLICA: Houve 1008 opiniões sobre a recomendação preliminar da Conitec, sendo 347 pelo formulário para contribuições técnico-científicas e 661 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Sendo que 1 concordou e 1007 discordaram. As 1007 contribuições foram avaliadas por descreverem os motivos de sua opinião em relação à recomendação inicial da Conitec. Os assuntos abordados pelos participantes foram: carga da doença da esclerose múltipla, preço do medicamento, acesso à saúde pelo SUS, pouco efeito colateral, facilidade na posologia e planejamento familiar. RECOMENDAÇÃO FINAL: o Plenário da Conitec, em sua 109ª Reunião Ordinária, no dia 09 de junho de 2022, deliberou por maioria simples, recomendar a não incorporação da cladribina oral para o tratamento de pacientes com esclerose múltipla remitente recorrente altamente ativa no SUS. Os membros da Conitec consideraram que não há evidência suficiente de que a cladribina oral seja similar ao natalizumabe e após discussão das contribuições públicas e nova proposta econômica do demandante, e a incerteza poderia ter impacto orçamenteario incerto no SUS. Por fim, foi assinado o Registro de Deliberação nº 745/2022. DECISÃO: Não incorporar a cladribina oral para o tratamento de primeira linha de pacientes com esclerose múltipla remitenterecorrente altamente ativa, no âmbito do Sistema Único de Saúde - SUS conforme a Portaria nº 66, publicada no Diário Oficial da União nº 129, seção 1, página 77, em 11 de julho de 2022.

An Innovative Approach to Modelling the Optimal Treatment Sequence for Patients with Relapsing-Remitting Multiple Sclerosis: Implementation, Validation, and Impact of the Decision-Making Approach.

INTRODUCTION: An innovative computational model was developed to address challenges regarding the evaluation of treatment sequences in patients with relapsing-remitting multiple sclerosis (RRMS) through the concept of a 'virtual' physician who observes and assesses patients over time. We describe the implementation and validation of the model, then apply this framework as a case study to determine the impact of different decision-making approaches on the optimal sequence of disease-modifying therapies (DMTs) and associated outcomes. METHODS: A patient-level discrete event simulation (DES) was used to model heterogeneity in disease trajectories and outcomes. The evaluation of DMT options was implemented through a Markov model representing the patient's disease; outcomes included lifetime costs and quality of life. The DES and Markov models underwent internal and external validation. Analyses of the optimal treatment sequence for each patient were based on several decision-making criteria. These treatment sequences were compared to current treatment guidelines. RESULTS: Internal validation indicated that model outcomes for natural history were consistent with the input parameters used to inform the model. Costs and quality of life outcomes were successfully validated against published reference models. Whereas each decision-making criterion generated a different optimal treatment sequence, cladribine tablets were the only DMT common to all treatment sequences. By choosing treatments on the basis of minimising disease progression or number of relapses, it was possible to improve on current treatment guidelines; however, these treatment sequences were more costly. Maximising cost-effectiveness resulted in the lowest costs but was also associated with the worst outcomes. CONCLUSIONS: The model was robust in generating outcomes consistent with published models and studies. It was also able to identify optimal treatment sequences based on different decision criteria. This innovative modelling framework has the potential to simulate individual patient trajectories in the current treatment landscape and may be useful for treatment switching and treatment positioning decisions in RRMS.

Eficacia y seguridad de cladribina en el tratamiento médico oncológico de la leucemia de células vellosas / Efficacy and safety of cladribine in the medical oncological treatment of hairy cell leukemia

ANTECEDENTES: La leucemia de células vellosas es una neoplasia de linfocitos B pequeños que se caracteriza por la presencia de núcleos ovales indentados y citoplasma abundante. - Colocar la población esperada. La población a esperada en el INEN es de 2 pacientes al año, según reportes de la oficina de epidemiología. - La cladribina es un análogo de las purinas, aprobado por la FDA y EMA para el tratamiento de la LCV. - Un párrafo de sumarios, guías y ETS. El sumario de Uptodate indica el uso de análogos de purina como tratamiento de primera línea en pacientes con LCV sintomáticos. Se encontró que tanto ESMO como NCCN recomiendan cladribina como tratamiento de primera línea en pacientes con LCV, también está indicado el uso de pentostatina. METODOLOGÍA: Se realizó una búsqueda sistemática encontrando 1 RS-MS y 2 estudios del mundo real. RESULTADOS: La evidencia encontrada es de calidad muy baja, debido a que los principales estudios son ensayos clínicos de un solo brazo, alta heterogenidad, o estudios no experimentales. - Cladribina logra una alta tasa de respuesta (>95%), tasa de remisión completa (>80%) y un adecuado nivel de sobrevida global a los cinco años en pacientes con LCV. - La evidencia es limitada y de baja calidad probablemente al tratarse de una enfermedad rara, aunque consistente en cuanto a las altas tasas de respuesta observadas. El panel de ETS sugiere continuar con el uso de cladribina para LCV así como cumplir con las indicaciones dadas en la GPC INEN. CONCLUSIONES: La leucemia de células vellosas es una neoplasia de linfocitos B. Se hizo una búsqueda sistemática, encontrando 1 RS-MS y 2 estudios del mundo real. La evidencia encontrada es de calidad muy baja, debido a que los principales estudios son ensayos clínicos de un solo brazo, alta heterogeneidad, o estudios no experimentales. Cladribina logra una alta tasa de respuesta (>95%), tasa de remisión completa (>80%) y un adecuado nivel de sobrevida global a los cinco años en pacientes con LCV. Se sugiere continuar con el uso de cladribina para LCV así como cumplir con las indicaciones de inicio de tratamiento incluidas en la GPC INEN.

[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.

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.

Debería usarse Cladribine para el tratamiento de la esclerosis múltiple: primer episodio y para la enfermedad recurrente/recidivante? / Should Cladribine be used for the treatment of multiple sclerosis: first episode and for recurrent / recurrent illness?

CONTEXTO: Debería usarse Cladribine para el tratamiento de la esclerosis múltiple: primer episodio? Se sugiere NO usar como droga de primera opción en el tratamiento del primer episodio de esclerosis múltiple. Debería usarse Cladribine para el tratamiento de la esclerosis múltiple: remitente recurrente? Se sugiere utilizar como alternativa terapéutica via oral y de segunda línea en el tratamento de la esclerosis múltiple recurrente-remitente, teniendo en cuenta costo y factibilidad de implementación. BÚSQUEDA: Se realizó una búsqueda en Medline, Pubmed, Cochrane Library y Epistemonikos, priorizando las revisiones sistemáticas, ensayos randomizados controlados (ECA), evaluaciones de tecnologías sanitarias y evaluaciones económicas. MÉTODOS: P1: Primer episodio de esclerosis múltiple. P2: Paciente con esclerosis múltipl recurrente/recidivante. I: Cladribine oral. C: Placebo/tratamiento estándard. O: Progresión de enfermedad (progresión a CDMS) evaluado con : log HR seguimiento: media 48 semanas Evento adverso serio seguimiento: media 48 semanas EA serio más suspensión de medicación seguimiento: media 48 semanas. RESULTADOS: Cladribine comparado con placebo para primer episodios de esclerosis múltiple (primera línea). El riesgo en el grupo de intervención (y su intervalo de confianza del 95%) se basa en el riesgo asumido en el grupo de comparación y en el efecto relativo de la intervención (y su intervalo de confianza del 95%). Cladribine en esclerosis múltiple remitente recidivante: Evidencia directa. Cladribine comparado con PLacebo para Esclerosis múltiple: enfermedad recurrente/recidivante. El riesgo en el grupo de intervención (y su intervalo de confianza del 95%) se basa en el riesgo asumido en el grupo de comparación y en el efecto relativo de la intervención (y su intervalo de confianza del 95%). RECOMENDACIONES Y JUICIOS: Cladribine via oral para el primer episodio de esclerosis múltiple. La Cladribine oral podría ser efectiva para evitar la progresión a enfermedad crónica para el tratamiento del primer episodio de esclerosis múltiple. Por otra parte este tratamiento podría asociarse con eventos adveros serios que lleven a la interrupción del tratamiento. Ambas afirmaciones tienen baja certeza debido a sesgo y a presentarse un estudio único que compara Cladribine con placebo, financiado por la industria farmacéutica. Dado la incertidumbre existente en cuanto a efectividad y eventos adversos, sumado al elevado costo de implementación y difícil implementación, se recomienda la utilización de otras opciones disponibles para el tratamiento de la esclerosis múltiple en el caso de primer episodio. Cladribine via oral para RRMS. La evidencia directa muestra que Cladribine oral probablemente sea efectiva frente a placebo para evitar la progresión, actividad y recaídas a los 96 meses en el tratamiento de la RRMS. Estos hallazgos están sustentados en una moderada certeza de la evidencia y la misma proviene de un único estudio financiado por la industria farmacéutica. La evidencia indirecta provista por los metaanálisis en red (también financiados por la industria) muestra que la Cladribine tiene una efectividad similar a otras drogas de segunda línea como Alentuzumab y Natalizumab en el tratamiento de la esclerosis múltiple recurrente-remitente. Existe evidencia que el Cladribine podría ser costo efectivo frente al tratamiento con otras drogas de segunda línea (Natalizumab y Alentuzumab).

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.

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.

Characteristics and treatment patterns among US patients with hairy cell leukemia: a retrospective claims analysis.

AIM: Describe hairy cell leukemia (HCL) treatment patterns using a large, nationally representative US database. PATIENTS & METHODS: Adults newly diagnosed with HCL (1 January 2006 to 30 June 2014) with continuous health plan enrollment ≥180 days pre- and 90 days post-diagnosis were identified from the QuintilesIMS PharMetrics Plus Health Plan Claims Database. Treatment patterns by line of therapy were assessed over the variable follow-up. RESULTS: Among 749 HCL patients (77.4% male; mean age 55.6; mean 32.3 months follow-up), only 37.7% initiated first-line therapy during the available follow-up in a mean of 4.4 months following diagnosis; the majority (75.5%) received cladribine (mean duration 7.3 days). Thirty-eight patients (5.1%) received second-line treatment. CONCLUSION: Over 2.7 years follow-up, more than a third of patients initiated first-line therapy which appeared to provide a long-lasting response.

Treatment of hairy cell leukemia: long-term results in a developing country.

Twenty-nine consecutive patients with hairy cell leukemia (HCL) were treated in two institutions with interferon (IFN, n = 18) or cladribine (n = 11), between July 1987 and May 2011. Median age was 62 (range 29-83) years; there were 21 males and 8 females. Seven of the 18 patients in the IFN group (39%) achieved a complete remission (CR), whereas all the patients in the 2-CDA group entered a CR. Three patients in the 2-CDA group relapsed and needed an additional course of the drug, 2, 3 and 6 years after the initial one. The median overall survival (OS) of the whole group has not been reached, being above 217 months, the 217-month OS being 91%. The survival of patients treated with either IFN or 2-CDA was not statistically different (94% OS at 217 months versus 91% OS at 133 months, respectively). The data that we present here suggest that treatment of HCL with either 2-CDA or IFN is equally effective; treatment costs with IFN are substantially lower than those of the purine analog.

Reduction in healthcare and societal resource utilization associated with cladribine tablets in patients with relapsing-remitting multiple sclerosis: analysis of economic data from the CLARITY Study.

BACKGROUND: Multiple sclerosis (MS) is a common, chronic, neurodegenerative condition associated with substantial healthcare and societal economic burden. Disease-modifying MS treatments have the potential to reduce health resource utilization (HRU), thereby reducing the attendant socioeconomic burden. OBJECTIVE: This study aimed to compare health and societal resource use and productivity in patients with relapsing-remitting MS (RRMS) receiving cladribine tablets versus placebo over 96 weeks in the CLARITY study. METHODS: The CLARITY study was a 96-week, randomized, double-blind, placebo-controlled study in patients with RRMS. HRU data, societal resource use and productivity data were collected at baseline and during scheduled patient visits, at 6-month intervals. The recall period for the HRU questionnaire was 3 months. The study was carried out at 155 sites across 32 countries worldwide. The intent-to-treat population comprised 1326 patients with RRMS randomized to cladribine 3.5 mg/kg (n = 433) or 5.25 mg/kg (n = 456) tablets or placebo (n = 437). Patient subgroups with high baseline disease activity were identified based on criteria of ≥2 relapses in the previous year (n = 392); ≥1 T1 gadolinium-enhancing (Gd+) lesion (n = 413); and ≥2 relapses in the previous year plus ≥1 T1 Gd+ lesion (n = 138). Cladribine tablets were administered in two (3.5 mg/kg group) or four (5.25 mg/kg group) short courses given at 4-week intervals at the start of a 48-week treatment period, followed by another two courses at the start of a subsequent 48-week re-treatment period. Interferon-ß rescue therapy was permitted from week 24. Intravenous corticosteroids were available for the treatment of neurological relapses. HRU outcomes included mean number of hospital days and emergency room (ER), clinic and home visits during each study period. Societal resource use and productivity outcomes included mean number of hours and days of paid assistance, mean patient and carer work days missed, and self-reported productivity. RESULTS: The mean number of hospital days per patient over 96 weeks was lower in the cladribine tablets groups (3.5 mg/kg group: -3.19 days; 5.25 mg/kg group: -1.54 days [both p < 0.01]) versus placebo. Likewise the mean number of ER visits was lower in both cladribine tablet groups compared with placebo (3.5 mg/kg group: -0.09 visits; 5.25 mg/kg group: -0.11 visits [both p < 0.01]), and the mean number of clinic visits was also lower in both cladribine tablet groups (3.5 mg/kg group: -0.68 visits; 5.25 mg/kg group: -0.66 visits [both p = 0.01]). Furthermore, treatment with cladribine tablets was associated with reduced mean numbers of missed work days for patients (3.5 mg/kg group: -2.42 days [p < 0.01]; 5.25 mg/kg group: -0.60 days [p = 0.50]). Corticosteroid use was lower amongst patients in the cladribine tablet groups than in the placebo group. The reduction in hospital days following treatment with cladribine tablets was also observed in patients with high disease activity at study baseline. CONCLUSION: This study provides evidence that the efficacy of cladribine tablets observed during the CLARITY study was associated with a reduced consumption of healthcare resources and a decreased need for medical and societal support. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00213135; EudraCT number: 2004-005148-28.