Background
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system that causes neurological disabilities, especially in young adults [
1]. The incidence of MS is increasing worldwide, with two million cases reported in 2016 [
2]. The prevalence and incidence of MS varies according to country and geographical areas [
3]. The prevalence of MS is higher in Europe and the United States compared to that in Asia [
4]. The estimated prevalence and incidence of MS in Thailand were 0.201 per 100,000 people and 0.073 per 100,000 person-years, respectively [
5]. Chronic disease progression results in a significant increase in disability, leading to economic and social burdens [
6]. Therefore, most patients who are unable to access MS treatment are affected by neurological disabilities, poor quality of life, and an additional socioeconomic burden [
7].
Disease-modifying therapy (DMT), which includes injectable platform therapies, oral medication, or monoclonal antibodies, has been proven to prevent relapse and patient disabilities [
8]. However, the cost associated with DMT is the most critical barrier preventing access to treatment [
9]. The price of DMT approved by the Thai Food and Drug Administration (FDA) ranges from 39,544 to 61,714 Thai baht (THB) per month, which is equivalent to 1,041 − 1,625 United States dollars (USD), whereas the average Gross National Income (GNI) per capita of the Thai population is only 18,888 THB per month (497 USD). According to a recent survey by the Multiple Sclerosis International Federation (MSIF) [
9], out of all the 102 countries where rituximab has been approved for the treatment of lymphoma and rheumatoid arthritis, 70 of them (including Thailand) have adopted it as off-label treatment for MS, because the benefits were considered to outweigh the need for regulatory approval [
10]. Previous studies from several countries have suggested that rituximab is not only safe and highly effective in the control of MS progression [
11‐
20], but it also has a lower cost than the currently approved DMT. The approximate annual cost of MS therapy in Thailand with the original rituximab is 100,000 THB (2,633 USD). However, a rituximab biosimilar is readily available in the country, and its efficacy has been shown to be similar to the original drug in the treatment of diffuse large B-cell lymphoma and severe rheumatoid arthritis [
21,
22]. The current cost of therapy for the same period of time with the rituximab biosimilar is only 27,000 THB (711 USD).
Until recently, only a small minority of patients with MS in Thailand could get access to FDA-approved DMTs or to rituximab therapy, as neither of these treatments have been included in the National List of Essential Medicines (NLEM). This pharmaceutical reimbursement list is used by all Thai health insurance schemes, including the Civil Servant Medical Benefit Scheme (CSMBS) for government officers and their dependents (9%), the Social Security Scheme (SSS) for private employees (16%), and the Universal Coverage Scheme (UCS) for the general population (75%) [
23]. The decision-making process to add a drug to the NLEM, especially one associated with high costs, requires the previous collection of efficacy, safety, cost-effectiveness, and budget impact information [
24]. Although three cost-utility analyses of DMT in Thai patients with MS suggested that DMT would not be cost-effective at the willingness-to-pay (WTP) threshold estimated for the country of 160,000 THB (4,214 USD) per quality adjusted life year (QALY) gained [
25‐
27], the cost-effectiveness of rituximab as an alternative has not yet been investigated. Therefore, the objective of this study was to evaluate the cost-utility of rituximab compared with best supportive care (BSC), the current standard practice for the treatment of patients with MS in Thailand. In addition, the budget impact for patients with MS if rituximab were to be included in the NLEM was estimated. The results of this study could inform decision-making on the potential inclusion of rituximab in the NLEM.
Discussion
Regardless of the evidence indicating that DMT can prevent hospitalization and relapse as well as decrease disability in MS patients [
8], most MS patients in Thailand are still unable to afford these expensive treatments, especially in low- or low-to- middle-income countries. In Thailand, DMT has not been included in the NLEM, as previous cost-effectiveness studies have suggested that it is not cost-effective. Currently, rituximab in both original and biosimilar forms has been approved for the treatment of lymphoma and rheumatoid arthritis but not MS in Thailand. Nevertheless, it has been used as an off-label treatment for patients with MS in clinical practice. Given that no cost-effectiveness information regarding the use of rituximab for MS treatment specific to Thailand has been reported, the drug has not been included in the NLEM, a pharmaceutical reimbursement list for all health insurance schemes in the country. Therefore, the Subcommittee for the Development of NLEM requested cost-effectiveness information on rituximab in order to consider whether it should be included into the NLEM. To the best of our knowledge, this study is the first to evaluate the cost-utility of rituximab compared to BSC in Thai patients with MS.
Our study suggests that the rituximab biosimilar would be dominant or cost-saving, indicating a lower cost but a higher effectiveness compared to BSC for MS treatment in Thailand. This study also demonstrated that the rituximab biosimilar has a high probability of being cost-effective compared with BSC, the current standard of treatment in the Thai healthcare system. The estimated budget impact of the rituximab biosimilar in patients with MS was approximately 25,000,000 THB per year during five consecutive fiscal years. In contrast, the original rituximab would not be cost-effective in the Thai context compared to BSC. Consequently, the results of this study could help inform policymakers on the potential advantages of including the rituximab biosimilar in the NLEM for MS treatment.
In support of this recommendation, it is worth mentioning that the use of rituximab in patients with MS is a common clinical practice in developed countries. For example, the efficacy of rituximab in reducing MS relapse has been supported by phase I and II clinical trials since 2008 [
34,
40]. However, although phase III clinical trials on the effectiveness of this drug to manage patients with MS have not been performed, it has nevertheless been regularly prescribed to these patients during the past five years in several countries, including Sweden [
18], the US [
16,
20], Spain [
17], Switzerland [
15], France [
12], Italy [
13], Germany [
41] and Lebanon [
14]. Notably, based on the clinical guidelines of the Middle East and North Africa Committee (MENACTRIMS) Consensus, rituximab is recommended as an off-label treatment for patients with highly active MS disease. Moreover, it should be administered as an escalation treatment to patients with all levels of MS in special populations such as refugees or in countries where other proper MS treatments are not accessible [
42]. In addition, according to the most recently updated guidelines from the American Academy of Neurology (AAN) published in 2018, rituximab is possibly more effective than placebo in reducing the risk of relapse at one year for patients with RRMS [
43]. The efficacy of rituximab compared with the FDA-approved DMT, (i.e., dimethyl fumarate) has been confirmed through a phase III randomized controlled trial [
35]. Therefore, this study can be considered as additional evidence on the advantages of including a rituximab biosimilar in the NLEM for the specific purpose of MS treatment. However, several considerations should be considered by physicians before prescribing rituximab or a biosimilar drug to MS patients, including side effects, disease activity, and off-label medication use in the treatment of MS.
Furthermore, the one-way sensitivity analysis indicated that the most sensitive parameter was the probability of relapse. The results indicate that treating patients with MS that experience frequent relapses may be a cost-saving intervention compared with BSC. In contrast, rituximab biosimilar would not be cost-effective in patients with few relapses. This could be explained by the fact that rituximab is particularly effective in patients with high disease activity. This is in line with the recommendations of several MS treatment guidelines [
43,
44], as physicians tend to use DMT only in MS patients with active disease.
Some limitations of this study need to be addressed. First, the transitional probabilities of rituximab to prevent relapse and disability progression were obtained from only two randomized controlled studies, which were the best available evidences on the effect of rituximab in patients with MS to date [
34,
35]. In 2008, a phase II double-blind randomized controlled trial [
34] revealed the safety and efficacy of rituximab compared with placebo in patients with RRMS; more recently, a phase III randomized controlled trial from 2022 demonstrated that rituximab is safe and effective compared with dimethyl fumarate [
35]. Second, we assumed that rituximab and its biosimilar had similar efficacy for MS treatment, since no head-to-head comparison between the two for the specific purpose of MS treatment is available in the literature. Nevertheless, the efficacy of the rituximab biosimilar in patients with diffuse large B-cell lymphoma [
21] and severe rheumatoid arthritis [
22] has been shown to be similar in pharmacokinetic studies. Third, due to the lack of data from Thailand, all transition probabilities for each health state were obtained from prospective longitudinal cohort studies published in other countries. Therefore, these parameters should be collected from local data in future studies. Fourth, as there is no data on disutility due to MS relapse available in Thailand, we obtained the relevant data from a UK study [
39], which is the only available source to date. Thus, the utility of MS patients with relapse in Thailand should be the focus of future studies. Finally, it should be noted that as there is no clinical data of MS patients in Thailand, we could not validate the prediction of the model. However, we performed model validation via the face validity method through consultations with clinical experts and health economists on the appropriateness of model structure, parameters used, and data sources. Model validation should be performed in future studies. Moreover, we did not investigate how appropriate the cut-off scores were in the Markov model, which warrants further research.
In conclusion, this study demonstrated that, in the context of the Thailand healthcare system, treatment with a rituximab biosimilar was cost-saving and exhibited a high probability of being cost-effective when compared with the current practice. The estimated budget impact of treating patients with active RRMS were 26,360,000 THB (844,255 USD), followed by 23,080,000 THB (739,388 USD), 22,400,000 THB (717,603 USD), 21,640,000 THB (693,223 USD), and 20,810,000 THB (666,608 USD) during five consecutive fiscal years, respectively. This study may encourage policy decision makers to extend the indications of including rituximab biosimilar in the NLEM to treat patients with MS.
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