Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand: Economic evaluation and budget impact analysis

Saharat Aungsumart; Metha Apiwattanakul

doi:10.1371/journal.pone.0229028

. 2020 Feb 12;15(2):e0229028. doi: 10.1371/journal.pone.0229028

Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand: Economic evaluation and budget impact analysis

Saharat Aungsumart ^1,^*, Metha Apiwattanakul ¹

Editor: Massimo Filippi²

PMCID: PMC7015451 PMID: 32050011

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory condition of the central nervous system. The extent of disability depends on the severity of the disease and the number of relapses. Although azathioprine is currently the main treatment for patients with NMOSD in Thailand, patients often relapse during its use. Hence, it is argued that there are other drugs that would be more effective. The purpose of this study is to evaluate, from a societal perspective and from the economic impact on Thailand’s healthcare system, the cost utility of treatment with mycophenolate mofetil (MMF) and rituximab in patients resistant to azathioprine. The Markov model with a one-year cycle length was applied to predict the health and cost outcomes in patients with NMOSD over a lifetime. The results showed that rituximab exhibited the highest quality-adjusted life year (QALY) gains among all the options. Among the rituximab-based treatments, the administration of a rituximab biosimilar with CD27⁺ memory B cell monitoring proved to be the most cost-effective option. At the willingness-to-pay threshold of 160,000 Thai baht (THB), or 5,289 US dollar (USD), per QALY gained, the treatment exhibited the highest probability of being cost effective (48%). A sensitivity analysis based on the adjusted price of a generic MMF determined that the treatment was cost effective, exhibiting an incremental cost-effectiveness ratio of -164,653 THB (-5,443 USD) and a 32% probability of being cost effective. The calculated budget impact of treating patients resistant to conventional therapy was 1–6 million THB (33,000–198,000 USD) for the first three years, while after the third year, the budget impact stabilized at 3–4 million THB (99,000–132,000 USD). These data indicate that, in Thailand, treatment of drug resistant NMOSD with a rituximab biosimilar with CD27⁺ memory B cell monitoring or treatment with a generic MMF would be cost effective and would result in a low budget impact. Therefore, the inclusion of both the rituximab biosimilar and a generic MMF in the National Drug List of Essential Medicine for the treatment of NMOSD may be appropriate.

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a devastating central nervous system (CNS) inflammatory demyelinating disease that is caused by autoantibodies targeting aquaporin-4 immunoglobulin G (AQP4-IgG) [1]. Patients usually present with severe optic neuritis and myelitis, which can cause blindness and quadriplegia [2]. The extent of the disability depends on the number and severity of relapses. Therefore, the mainstay of therapy is effective relapse prevention and aggressive treatment during attacks. Furthermore, severe attacks are typically managed by treatment with high dose steroids followed by a plasma exchange to rescue neurological function [3]. Accordingly, the cost of treatment is higher in patients with acute severe attacks compared to those with mild attacks for whom high dose steroid therapy is usually sufficient. Moreover, the efficacy of plasma exchange is limited, as only some patients exhibit fully restored neurological function [3–5]. Thus, relapse prevention with immunosuppressive drugs is the most effective treatment. Commonly used drugs for the prevention of NMOSD relapse include prednisolone, azathioprine, mycophenolate mofetil (MMF), and rituximab [6]. There is evidence that rituximab and MMF exhibit greater efficacy compared to azathioprine [7, 8]. Highly efficacious medications not only reduce the number of relapses but also limit the severity of the relapses [9]. However, due to the high cost of rituximab and MMF, azathioprine is the only drug included on the National Drug List of Essential Medicine (NLEM) for the prevention of NMOSD relapses in Thailand. The main objective of this study was to evaluate the cost effectiveness of rituximab and MMF in the treatment of NMOSD patients. The second objective was to estimate the budget required for alternative treatments for NMOSD patients in Thailand.

Materials and methods

This study used a Markov model to compare the lifetime costs and outcomes of patients with NMOSD undergoing different treatments. Specifically, rituximab and MMF were evaluated in comparison to azathioprine. The study was conducted from a societal perspective, as recommended by the guidelines of the health technology assessment (HTA) of Thailand [10]. The target population consisted of NMOSD patients older than 18 years. In the economic analysis, azathioprine was used as the reference (option 1). In addition, rituximab treatments were classified into two categories, depending on the method used for the administration of the drug. The first regimen (option 2) consisted of a fixed dose of rituximab, which began with the introduction of two 1000 mg intravenous rituximab doses two weeks apart followed by 1000 mg intravenous rituximab doses every six months. The other method, which was based on the monitoring of CD27⁺ memory B cells (option 3), consisted of the administration of 375 mg/m² rituximab every week for four weeks, along with the monitoring of CD27⁺ memory B cells every three months. If the CD27⁺ memory B cell counts in the peripheral blood exceeded 0.05% of the total mononuclear cells, the patient was infused with additional rituximab at 375 mg/m² [11]. Moreover, since an equally effective rituximab biosimilar is available in Thailand at a lower price, the latter compound was also evaluated using the fixed-dose regimen (option 4) and the method based on dose adjustment following the CD27⁺ memory B cell assessment (option 5). Finally, the administration of a 2000 mg dose of MMF per day (option 6) was included in the cost-effectiveness analysis, in which the future outcomes and costs were discounted at a rate of 3% to conform to present day values. The data were collected and analyzed with Excel (Microsoft, Redmond, WA, USA). The outcomes were estimated based on quality-adjusted life years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) was expressed in Thai baht (THB) per QALY gained. The cost-effectiveness was determined by applying a ceiling threshold of 160,000 THB (5,289 USD) per QALY gained, as recommend by the Subcommittee for the Development of the National List of Essential Medicines (NLEM) [10].

Economic model

The Markov model shown in Fig 1 was used to simulate the clinical course of patients with NMOSD and to estimate the health outcomes and costs over a lifetime horizon based on a cycle length of one year. The study compared five different treatment options, with azathioprine as the reference. Three main health states based on the EDSS were considered, namely, (i) patients with no or mild disability (Expanded Disability Status Scale (EDSS) 0–5.5); (ii) patients with moderate to severe disability (EDSS 6–9.5); and (iii) deceased NMOSD patients. In addition, two health stages that were represented by NMOSD patients temporarily experiencing a mild or severe relapse (temporary stage) were included in the model. These conditions reflect the natural history of patients with NMOSD. Furthermore, relapse classification according to severity was justified by both clinical and economic considerations. Patients exhibiting a severe relapse were defined by a severe disability that was sustained or worsened after taking high dose steroids as indicated by EDSS scores ≥ 7.0 in patients who presented with myelitis or in patients with a visual acuity worse than 20/200 who presented with optic neuritis (4). These groups require more expensive treatments and exhibit lower utility compared to those diagnosed with mild relapse. The temporary stage group included (iv) patients with no or mild disability and mild relapse, (v) patients with no or mild disability and severe relapse, (vi) patients with moderate or severe disability and mild relapse, and (vii) patients with moderate or severe disability and severe relapse. The arrows in Fig 1 denote permissible transitions.

There are several assumptions inherent to this model. First, relapse is classified according to severity. A patient undergoing a severe relapse requires treatment with high dose steroids plus a plasma exchange and frequent physiotherapy, thus implying higher costs compared to patients for whom high dose steroids alone are sufficient. Second, the same probability of relapse was assumed for all the patient groups. Third, whereas NMOSD patients experiencing mild relapse return to the previous health stage after treatment, some patients undergoing severe relapse die while others progress to severe disability. Fourth, surviving patients with moderate or severe disability who experience severe relapse return to the previous health stage. Fifth, patients with moderate or severe disability cannot return to the state of no or mild disability, thus indicating a confirmation of disability progression following a severe relapse.

Cost variables

Data regarding the direct medical and nonmedical costs of patients with NMOSD were collected at the Prasat Neurological Institute, a tertiary neurological referral center [12]. In brief, this was a cross-sectional study for which patients were recruited between November 1, 2015, and June 30, 2016. Of the 36 patients included in this study, 87% were AQP4 antibody-positive. The average age and average age at onset were 48.48 ± 12.00 and 39.48 ± 12.24 years, respectively. The percentage of female patients was 95.4%. The annualized relapse rate (ARR) was 0.53 ± 0.29. Twenty-five patients diagnosed with severe relapse NMOSD required a plasma exchange, four patients exhibited a mild relapse, and seven patients exhibited no relapse. Because 13% of the cohort were seronegative AQP4 patients, there were some differences in the demographic data of these patients compared with the entire cohort. These differences include a higher percentage of male patients (50%), lower average age and lower average age at onset, i.e., 30.75 ± 8.90 and 24.75 ± 7.9 years, respectively, and lower average ARR (0.35 ± 0.17) compared to the entire cohort. However, the severity of relapse of the seronegative group as indicated by the EDSS and visual acuity scores at the time of relapse was similar to that of the seropositive groups. This result occurred because the selection process required that the health status of the patients be severe enough to perform plasmapheresis. The consumer price index was used to adjust all the costs to the year 2019 values. The exchange rate of 30.3 THB to one US dollar (USD) was used in this study.

Drug costs were obtained from the reference price database of Thailand [13], while other direct medical costs were retrospectively retrieved from the electronic medical records of the patients. All charges were adjusted to a cost-to-charge ratio of 1.63[10]. The costs of hospitalization due to relapse were classified according to the severity of the attack. The direct nonmedical costs, such as food, accommodations, transportation, and formal and informal care, were collected through interviews with patients via a structured questionnaire. To avoid double counting and based on the Thai HTA guidelines, the indirect costs were not included in this study [10].

Clinical variables

The efficacy of azathioprine relative to rituximab in preventing relapse and the associated probability of achieving a relapse-free status were obtained from a single randomized control study published by Nikoo et al. [14]. Although a systematic review and meta-analysis regarding the ability of rituximab to prevent NMOSD relapse was published [15], we did not use this meta-analysis due to the heterogeneity of the various study designs. There was also no information regarding relapse-free cases, and some of the analyses in the aforementioned study were not comparable. Data on the efficacy of MMF compared to azathioprine with respect to the ability to yield a relapse-free status were obtained by a systematic review and meta-analysis, in which five studies were selected and included in the pooled analysis via the Stata v16.0 (StataCorp LLC, College Station, TX, USA) (S1 Fig). The details and flow chart of our study selection are reported in the supplementary S1 Text. Moreover, data on the efficacy of rituximab and MMF in preventing severe relapse, relative to azathioprine, were obtained from a single retrospective study conducted by Jeong I. H. et al. [9].

The probabilities of severe relapse, mild relapse, and death due transitioning to relapse were obtained from the Prasat Neurological Institute between October 1, 2017, and September 30, 2018 [16]. In summary, there were 49 acute NMOSD attacks that consisted of 25 cases of first attack and 24 cases of relapse. Severe relapse occurred in 4 of the 24 cases, and one patient died due to a severe attack. All of these NMOSD patients were AQP4 antibody positive. The average age and age at onset were 46.30 ± 11.93 and 42.02 ± 13.43 years, respectively. The percentage of female patients was 93.9%. The ARR was 0.70± 0.41 per year. We posit that the reason to use this cohort rather than the 36 patients in the previous study [12] to determine the probability of transition is because these data were collected in a prospective manner and include all of the NMOSD relapse patients who were treated at the Prasat Neurological Institute during the referenced period. Thus, these data are more realistic for the incidence of relapse, proportion of severe relapse, and incidence of death due to NMOSD relapse. Data on the efficacy of plasmapheresis in Thailand were used to derive the probability of progressing to moderate and severe disability after a severe relapse [4]. The all-cause mortality data in the Thai population by age group were obtained from the life table data provided by the World Health Organization [17]. The standard mortality ratio (SMR) among patients with moderate to severe disability was 2.78 times higher than the SMR in the general population [18].

Health outcomes

The health outcomes were expressed as QALYs gained and were defined as the number of years spent in each health state multiplied by the utility score. The utility of patients with NMOSD in Thailand was obtained from a previously published multicenter cross-sectional study [19], while that of patients with NMOSD relapse was obtained from another study [12]. In brief, the utility data from 29 relapsing NMOSD patients was obtained through interviews using a Thai version of the EuroQol Five Dimension Questionnaire that included five levels (EQ-5D-5L). The quality of life (QoL) losses due to severe and mild relapse were –0.29 and –0.07, respectively. All the input parameters of the models are shown in Table 1.

Table 1. Cost and input parameters of decision models.

Cost and input parameter	Distribution	Mean	Standard deviation	Reference
Discounting
Discount rate for costs (%)		3	(0–6)
Discount rate for outcomes (%)		3	(0–6)
Efficacy of medication in relapse prevention
Azathioprine	Beta	0.41	0.242	[14]
MMF	Beta	0.46	0.248	[7–9,20,21]
Rituximab	Beta	0.65	0.228	[14]
Efficacy of medication in prevention of severe relapse
Azathioprine	Beta	0.17	0.139	[16]
MMF	Beta	0.028	0.032	[9]
Rituximab	Beta	0.014	0.017	[9]
Transition probability after severe relapse
Progression to disability after relapse	Beta	0.190	0.02	[4]
Death due to relapse	Beta	0.02	0.002	[16]
Total direct medical cost of treatment in one year (THB)
Severe relapse	Gamma	395,351	111,506	[12]
Mild relapse	Gamma	34,293	6,885	[12]
No relapse	Gamma	11,401	11,332	[12]
Total direct nonmedical cost of treatment in one year (THB)
Severe relapse	Gamma	24,640	4,928	[12]
Mild relapse	Gamma	7,261	1,452	[12]
No relapse	Gamma	2,650	530	[12]
Utility of patients with NMOSD
Normal-mild disability	Beta	0.515	0.010	[19]
Moderate-severe disability	Beta	0.073	0.014	[19]
Disutility after relapse
Mild relapse	Beta	0.07	0.04	[12]
Severe relapse	Beta	0.29	0.07	[12]
Cost of medication in one year (THB)
Azathioprine	Gamma	3,978	795	[13]
MMF	Gamma	64,240	12,848	[13]
Rituximab^* (CD27⁺ memory B cell count monitoring)	Gamma	194,607^a	38,921	[13]
Rituximab^* (CD27⁺ memory B cell count monitoring)		68,869^b	19,345
Rituximab (fixed dose)	Gamma	145,092^a	29,018	[13]
Rituximab (fixed dose)		96,728^b	19,346
Rituximab biosimilar^* (CD27⁺ memory B cell count monitoring)	Gamma	158,070^a	31,614	[13]
		56,690^b	11,338
Biosimilar Rituximab (fixed dose)	Gamma	116,070^a	23,214
Biosimilar Rituximab (fixed dose)		77,380^b	15,476	[13]

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* Based on CD27⁺ memory B cell monitoring four times per year with two additional rituximab administrations

^a Cost of medication in the first year

^b Cost of medication in the following years

Uncertainty analysis

Probabilistic sensitivity analyses (PSA) were performed to simultaneously test the uncertainty of all the parameters. The Monte Carlo method was run for 1,000 simulations. The results of the PSA were expressed as cost-effectiveness acceptability curves. To identify the best candidate treatment option with respect to cost effectiveness, one-way sensitivity analyses were conducted to evaluate the uncertainty of each parameter. The results are presented as Tornado diagrams.

Budget impact analysis

The budget impact analysis was based on an estimated population of 69 million [22] and on the prevalence rate of NMOSD [23]. The following criteria were used for the analysis: (i) patients resistant to the first-line treatment (azathioprine) who were previously studied at the Prasat Neurological Institute, Thailand [24]; (ii) a treatment coverage rate of 30% for each year; (iii) a treatment coverage rate of 100% in three years (iv); a closed cohort model, and (v) a no cost discount.

Institution review board

This study was approved by the Institutional Review Board of the Prasat Neurological Institute approval number 61–437207(14). Written informed consent was obtained from all the enrolled patients.

Results

Cost-utility analysis

Our model simulated the lifetime of NMOSD patients undergoing six different treatment options. The cumulative costs, QALYs, and ICER are shown in Table 2 and Fig 2. Rituximab had the highest QALY gains compared to the other options. Among the rituximab treatments, the administration of rituximab biosimilar with CD27⁺ memory B cell monitoring resulted in the lowest lifetime cost, i.e., 3,097,842 THB (102,408 USD). However, these data were based on the assumption that the biosimilar and its administration strategy exhibited similar efficacy to that of the original rituximab. The life years (LYs) gained from the rituximab-based regimen was 25.49, whereas the LYs associated with azathioprine and MMF were 24.29 and 25.34, respectively.

Table 2. Costs and outcomes for each medication are expressed in THB (USD).

Medication	Total cost THB (USD)	Total effectiveness		Incremental cost THB (USD)	Incremental effectiveness		ICER THB (USD)
Medication	Total cost THB (USD)	LYs	QALYs	Incremental cost THB (USD)	LYs	QALYs	LYs	QALYs
Azathioprine	3,665,371	24.29	8.40
Azathioprine	(120,969)
Rituximab fixed dose	4,156,051	25.49	12.31	490,681	1.20	3.91	408,455	125,530
Rituximab fixed dose	(137,163)			(16,194)			(13,480)	(4,143)
Rituximab CD27⁺ memory B cell regimen
	3,453,054	25.49	12.31	Dominant	1.20	3.91	Dominant	Dominant
	(113,962)
MMF (2000 mg/day)	3,746,932	25.34	11.52	81,561	1.05	3.12	77,741	26,159
MMF (2000 mg/day)	(123,661)			(2,692)			(2,566)	(863)
Biosimilar of rituximab fixed dose
	3,597,221	25.49	12.31	Dominant	1.20	3.91	Dominant	Dominant
	(118,720)
Biosimilar of rituximab CD27⁺ memory B cell regimen
	3,097,842	25.49	12.31	Dominant	1.20	3.91	Dominant	Dominant
	(102,239)

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In the cost-effectiveness plane (Fig 2), azathioprine served as the comparator treatment at a fixed point (0, 0). Compared to azathioprine, all the other options except for the fixed-dose original rituximab and MMF, resulted in lower costs and greater QALYs. The administration of the rituximab biosimilar with CD27⁺ memory B cell count monitoring yielded the lowest ICER, specifically, -145,190 THB (-4,799 USD) per QALYs gained. Thus, the latter was the most cost-effective option based on a ceiling threshold of 160,000 THB (5,289 USD) per QALYs gained, as recommended by the Subcommittee for the Development of the NLEM [10].

Uncertainty analysis

Fig 3 shows the cost-effectiveness acceptability curves for all treatment options. At the willingness-to-pay (WTP) rate of 160,000 THB (5,289 USD) per QALY gained, the results of the PSAs indicate that the administration of the rituximab biosimilar with CD27⁺ memory B cell monitoring has the highest probability of being cost effective (48%), followed by azathioprine (30%), MMF (13%), and original rituximab with CD27⁺ memory B cell monitoring (9%). The results of the one-way sensitivity analysis regarding the administration of the rituximab biosimilar with CD27⁺ memory B cell monitoring are presented in Fig 4. The ICER was most sensitive to variations in the cost due to severe relapse treatment, followed by the efficacy of rituximab in preventing relapse, discount rate for outcome, discount rate for cost, price of biosimilar rituximab, efficacy of rituximab in preventing severe relapse, utility of patients with moderately severe disability, and utility of patients with no or mild disability.

Sensitivity analysis based on the current price reduction for MMF

Due to the availability of generic MMF in Thailand, the purchasing price from the Prasat Neurological Institute on May 1, 2018, for a 250-mg tablet was 14.5 THB (0.48 USD) compared to 22 THB (0.73 USD) reference price listed in the database of the Drugs and Medical Supplies Information Center [13]. With respect to the MMF evaluation, the 14.5 THB (0.48 USD) tablets were considered in the model. The lifetime cost of MMF for NMOSD treatment decreased from 3,746,932 to 3,151,991 THB (123,866 to 104,198 USD). Accordingly, the new ICER generated by MMF was -164,653 THB (5,443 USD) (S2 Fig), which indicates that the use of MMF at the current price was cost effective, based on a ceiling threshold of 160,000 THB (5,289 USD) per QALY gained. The cost-effectiveness acceptability curves for all treatment options after applying the reduced MMF price are shown in S3 Fig. At the WTP rate of 160,000 THB (5,289 USD) per QALYs gained, the results of the PSA demonstrated that both MMF and azathioprine had a similar probability of being cost effective, i.e., 32%. The rituximab biosimilar and original rituximab administrations with CD27⁺ memory B cell count monitoring had cost-effectiveness probabilities of 31% and 5%, respectively.

Budget impact analysis

The budget impact (Table 3) was based on an NMOSD prevalence rate of 0.403 per 100,000 [23], which corresponds to approximately 280 NMOSD patients in a population of 69 million [22]. Azathioprine resistance was found in 30% of the Thai cohorts [24]. Eighty-four patients were identified as resistant to conventional NMOSD drugs. Assuming a coverage treatment rate of 35% in the first year, 70% in the second year, and 100% in the third year, the approximate incremental budgets for MMF, based on the 14.5 THB price, in the first and second years were 1,123,176 and 2,129,867 THB (37,130 and 70,409 USD), respectively. After the third year, the incremental budget was predicted to stabilize at 2,859,618 THB (94,533 USD). With respect to rituximab biosimilar administration with CD27⁺ memory B cell count monitoring, the approximate incremental budgets were 4,511,604, 5,938,445, and 6,604,285 THB (149,144, 196,312, and 218,323 USD) in the first, second, and third years, respectively. The budget was predicted to stabilize after the fourth year at 4,060,047 THB (134,216 USD).

Table 3. Budget impact of the adoption of new therapies for NMOSD in THB (USD).

Treatment		1^st Year	2^nd Year	3^rd Year	After 3^rd Year
Azathioprine		116,485	349,456	682,272	682,272
Azathioprine		(3,844)	(11,533)	(22,517)	(22,517)
MMF	Total price	1,239,662	2,489,323	3,541,890	3,541,890
	Total price	(40,913)	(82,156)	(116,894)	(116,894)
	Incremental budget	1,123,176	2,129,867	2,859,618	2,859,618
	Incremental budget	(37,069)	(70,293)	(94,377)	(94,377)
Biosimilar Rituximab	Total price	4,628,090	6,287,901	7,286,557	4,742,318
	Total price	(152,742)	(207,521)	(240,480)	(156,152)
	Incremental budget	4,511,604	5,938,445	6,604,285	4,060,047
	Incremental budget	(148,898)	(195,988)	(217,963)	(133,995)

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Discussion

The issues with respect to NMOSD have been acknowledged for more than a decade in Thailand, i.e., since the NMO-IgG test had been made available [25]. However, due to its low disease prevalence, patients are often overlooked and do not receive adequate attention from the national health system, e.g., in terms of reimbursement costs for the treatment of severe relapse or high-efficacy drugs for the prevention of relapse. In western countries, rituximab is regarded as the first-line therapy to prevent relapse and is used as a rescue therapy after another first-line therapy has failed. Although there is still no consensus [26,27], patients with NMOSD in western countries often have access to highly efficacious drugs for relapse prevention, with no consideration being given to its cost effectiveness by NMOSD patients. This is a very different situation from low- and middle-income countries where patients who suffer from the failure of first-line medications must continue with the same therapy due to the inaccessibility of high-cost drugs and thus suffer from the consequent inadequate relapse prevention and disability accrual. This is the first study to demonstrate that appropriate regimen adjustments may substantially increase the cost effectiveness of high-efficacy drugs in the treatment of NMOSD. This study provides new evidence regarding the economic impact associated with the extended application of high-efficacy drugs for patients with NMOSD and may be relevant for those making public health policy decisions.

In particular, this study demonstrates that at the current WTP threshold of 160,000 THB (5,289 USD), a rituximab biosimilar or generic MMF at the reduced price of 14.5 THB (0.48 USD)/250-mg tablet may be as cost effective as the current practice if the dose is calibrated based on disease activity as assessed by the CD27⁺ memory B cell count in the context of the Thai health care system. Our analysis further indicates that appropriate regimens of high-efficacy drugs may avoid the extra costs required for relapse treatment associated with plasmapheresis and prolonged hospitalization. We compared our study with a previous report focusing on the economic analysis of another idiopathic CNS demyelination in Thailand, i.e., multiple sclerosis (MS) [28]. The latter study demonstrated that the disease modified therapy for MS was not cost effective. However, in our study, the low cost of the rituximab biosimilar (one-tenth the current price of the disease modified therapy for MS) resulted in both cost effectiveness and cost savings. Similarly, MMF proved cost effective in our model, as the price of generic MMF is as low as 35% that of the standard price. Thus, for high-efficacy drugs, price is an important factor for cost effectiveness, especially in low- and middle-income countries.

A strength of our study is the classification of NMOSD relapse severity, which correlates with the actual cost of treatment, especially for patients who experience relapses during therapy. Patients with severe relapses require high-cost treatments, including plasmapheresis, and some may also require ventilation support because of respiratory failure. Treatment costs may also include those caused by complications related to prolonged hospitalizations, such as ventilator-associated pneumonia, urinary tract infections, and deep venous thrombosis. All of these additional costs could be avoided by preventing relapses or decreasing relapse rates in NMOSD patients.

In our model, the one-way sensitivity analysis demonstrated that the management of severe relapse had a strong impact on the ICER, thus reflecting the relatively high costs for this treatment. The wide range of 95% CI in our data, i.e., 176,799–613,902 THB (5,844–20,924 USD) reflects the individual differences among patients with severe relapse, such as the length of hospitalization or various complications. Another factor influencing the ICER is the efficacy of rituximab in relapse prevention, as patients with severe and mild relapse exhibited decreased utility, i.e., 0.29 and 0.07, respectively. Severe relapse also causes disease progression and, in some cases, death during the attack, all of which reflect the natural history and progression of NMOSD [29] and the high costs associated with severe relapse treatment. These data confirm that relapse prevention is the mainstay of treatment for patients with NMOSD.

Our budget impact analysis was based on the assumption that treatment coverage was 35% per year for patients who relapsed under conventional therapy. Nonetheless, there might be some variations in the budget impacts during the first three years to cover 35% to 100% of the patients with NMOSD, thus resulting in a 2- to 3-fold budget increase compared to the estimate, after which the budget impact is predicted to stabilize at approximately 3–4 million THB per year.

There are some limitations to this study. First, our model did not account for costs related to the adverse effects of medications. Second, the cost of rituximab treatment was calculated by assuming two additional administrations per year, whereas some patients may require more frequent administrations during the first few years. However, data from a 5-year follow-up study revealed that, on average, rituximab is administered eight times in five years (1.6 times per year) [11], which indicates that the actual drug cost may be even lower than that hypothesized by our model. Recent published data classified patients with NMOSD as clustered and nonclustered relapse patients, according to the number of relapse occurrences within 12 months of their previous attack [30]. In patients with cluster relapse, the high efficacy of medication should be considered because of the frequent relapses, whereas in the nonclustered group, the relapses were infrequent. These data indicate that it is possible to decrease preventive medication to lower costs during the nonclustered period. If we considered this strategy in our model, the cost of medication would be lower, and there would be a cost savings in the cost-effective analysis. Third, since NMOSD is a rare disease, some of the parameters may not be found in the literature, including the probability of death due to relapse [16], the probability of severe relapse requiring plasmapheresis [16], and the probability of disease progression after severe relapse [4]. These parameters were analyzed at our institute, which is a tertiary referral neurological center, so there is selection bias, particularly when considering the effect of the high proportion of patients with severe relapse. Fourth, we did not consider changes in therapy due to treatment failure, even though such changes may occur in clinical practice [6–9,31]. Fifth, including the different cohorts in the cost calculations, i.e., cohorts where 13% of the patients are in seronegative NMOSD groups and prospective cohorts are in transition, the probability calculations that include all seropositive NMOSD will influence the results. In other words, cost parameters generated by patient groups of mixed populations of seronegative NMOSD who exhibited lower relapse rates will lower the cost parameters more than expected. The patients in the seropositive NMOSD group who more frequently relapse will incur higher costs for both direct and indirect medical expenses compared with the seronegative patients. However, if we apply only AQP4 positive NMOSD in the cost calculations, using high efficacy medication will result in greater differences in reducing relapse frequency and in further reducing the costs associated with treatments. Hence, the ICER that generates this situation negatively impacts our results, which indicates greater cost savings when treating NMOSD with high efficacy medications. Finally, since disease relapse may occur 10 years after remission, a lifetime treatment period was applied in our model [32]. However, some of the patients might cease immunosuppressive treatment after disease onset, especially patients with prolonged disease quiescence [33]. An additional limitation in the budget impact estimation was that the hospital-based prevalence data might not reflect the prevalence of NMOSD patients in the general population. Furthermore, our estimation did not include newly diagnosed NMOSD cases because they exhibit a very low incidence rate in the patient population. Notably, only NMOSD patients who were drug-refractory for at least six months following their initial diagnosis were defined as drug resistant.

In conclusion, this study demonstrated that, in the context of the Thailand healthcare system, treatment with a rituximab biosimilar combined with disease activity monitoring of the CD27⁺ memory B cell count or treatment with a generic MMF were cost efficient and exhibited a high probability of being cost effective when compared with the current practice. The estimated budget impact of treating patients with NMOSD who are resistant to conventional therapy is 1–6 million THB (33,000–198,000 USD) during the first three years, after which the budget stabilizes at 3 to 4 million THB (99,000–132,000 USD), for MMF- and rituximab-based treatments, respectively. This study may encourage politicians to extend the indications of high-efficacy drugs for the prevention of NMOSD relapse to include rituximab and mycophenolate mofetil in the NLEM.

Supporting information

S1 Fig. Meta-analysis of mycophenolate mofetil in comparison to azathioprine in relapse-free NMOSD.

(TIF)

Click here for additional data file.^{(492.9KB, tif)}

S2 Fig. Cost-effectiveness plane.

Cost-effectiveness plane covering lifetime cost effectiveness of six treatment options for NMOSD, after MMF price adjustment to 14.5 THB. RTX: rituximab; MMF: mycophenolate mofetil; mCD27⁺ B cells: monitor CD27⁺ B cells.

(TIF)

Click here for additional data file.^{(1.1MB, tif)}

S3 Fig. Cost-effectiveness acceptability curves.

Acceptability curves of cost effectiveness at the different ceiling thresholds for six NMOSD treatment options, after the MMF price adjustment to 14.5 THB. RTX: rituximab; MMF: mycophenolate mofetil; mCD27⁺ B cells: monitor CD27⁺ B cells.

(TIF)

Click here for additional data file.^{(568.7KB, tif)}

S1 Text. Treatment efficacy of MMF.

(DOCX)

Click here for additional data file.^{(63.8KB, docx)}

Acknowledgments

This project is a continuation of the research from the 15^th Health Economic Evaluation Training Course organized by the Health Intervention and Technology Assessment Program (HITAP). The authors would like to thank Dr. Pritaporn Kingkaew (HITAP), who served as a consultant on this project.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This project received financial support from the Prasat Neurological Institute, Department of Medical Services, Ministry of Public Health Thailand. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0229028.r001

Decision Letter 0

Massimo Filippi

10 Dec 2019

PONE-D-19-28259

Cost-effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand:Economic evaluation and budget impact analysis

PLOS ONE

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Reviewer #1: In this work Angusmart and Apiwattanakul perform a cost-effectiveness analysis of different regimens of mycophenolate mofetil (MMF) and rituximab in neuromyelitis optica spectrum disorders patients resistant to azathioprine in Thailand. Authors conclude that rituximab has the highest quality-adjusted life year (QALY) and the better cost-effectiveness profile when its biosimilar is administered according to B cell CD27+ monitoring. Moreover, also generic MMF is cost-saving and effective. In this perspective, Authors suggest the inclusion of both rituximab biosimilar and generic MMF in their national drug list of essential medicines.

I agree with Authors and with their analysis. In NMOSD disability accrual is usually associated with relapses, so, it is likely that an adequate preventive therapy would reduce disability, hospitalization and their related costs. I have only several points which need a further clarification.

These are my comments.

Major points:

1. I have several concerns regarding the rituximab administration “1 g twice a week for six months”. Could you please add a reference? It is completely different from the usual regimen (1 g every six months). This latter approach would even ameliorate your cost-effectiveness analysis.

2. Authors should add a paragraph inclusive of a detailed description of NMOSD patients from the Prasat Neurological Institute who were used for the analysis, specifying the type of analysis (i.e. cost variables evaluation, clinical variable evaluation). For instance, it is not clear why Authors used 36 patients for the evaluation of direct medical and non-medical costs and 49 for the estimation of transition probabilities of relapses and death). Moreover, it is never specified whether all patients are seropositive and their annual relapse rate.

3. Add a definition of relapse severity (i.e. a severe relapse requires both steroid treatment and plasma exchange and an EDSS of XX). I suppose you used such definitions to infer direct medical and nonmedical costs from the Prasat Neurological Institute?

4. Figures quality: Authors should provide better figures of higher quality (they appear grainy), should not use symbols like “_” between words and a color scale would make the meaning of pictures more immediate. Moreover, pay attention to list the entire acronyms in figures legends.

Minor points:

1. Introduction: add a reference when state that severe relapse is treated with high-dose steroids followed by plasma exchange (according to Abboud et al., MSJ 2016, plasma exchange should be started early).

2. Introduction: MMF and NLEM were never cited “in extensor” before the acronym

3. Introduction: “Not only for the number of relapse but also the relapse severity”. Consider reword the sentence (it has no verbal predicate).

4. In order to favour the comprehension of the work also among Europeans and Americans, I would add the conversion of Thai Bath in Western currency (i.e. euros or dollars).

5. Cost variables: “The indirect costs not include in the study to avoid double counting”. Please reword the sentence (what do you mean? That indirect costs was not included?).

6. Table 3: NMOSDD should be changed in NMOSD.

7. Discussion: “Although the burden of NMOSD was known and recognized disease more han decate in Thailand.” Consider to write a new sentence, this lacks predicates.

8. Discussion: I would change “policy makers” into politicians.

Reviewer #2: General comment:

At first glance, the manuscript seemed to deal with a very regional topic and not suitable for the journal. However, after consideration, I feel the manuscript is dealing with an important topic in the field of medical economics with potential for further development. Although the model they built contains many flaws from clinical viewpoint, this type of research may expand the possibility of future researches in the field of clinical neurology. Nevertheless, whether this study is “scientific” or not is unsure.

Major comments:

1. The English throughout the manuscript is not well written. There are many grammatical errors. I strongly recommend the authors to undergo a native check.

2. Was there no previous report or systematic review that evaluated the effect of long-term low-dose oral prednisolone? I heard that oral PSL is in the first-line in some countries. If possible, I want to know the location of oral PSL on the plane of Figure 2.

3. What kind of statistical software did you utilize for this study? Matlab or SPSS? Please clarify in the manuscript.

4. What is the mainstay of relapse prevention for NMOSD patients in Western countries? Do they also utilize azathioprine for the first line therapy? Please describe in the introduction or in the discussion.

5. Where are the legends for figures and tables? Please spell out the abbreviations in the figures and tables.

Minor comments:

1. Page 4: “rituximab (1gm)” is to be changed to “(1mg)”?

2. Page 4-5: Is there an evidence to divide “mild” and “moderate” disability at EDSS 5.5? EDSS 5.5 seems more than “moderate” disability to me. I am not sure about this point, so you can ignore this comment if it is too hard to answer.

3. Page 5: Is it OK not to divide the relapse phenotypes into ON (optic neuritis), myelitis, and CVOs lesions? EDSS scoring deals with this point on the same dimension, but this could cause some bias to your research.

4. Page 6: Were all enrolled NMOSD patients positive for the serum anti-AQP4 antibody?

Were they also screened for serum anti-MOG antibody?

5. Page 6: As to the cost, did you take the cost of regularly monitoring CD27+ memory B cells? Is it easily monitored in all tertiary hospitals without paying extra fee in your country?

6. Page 7: The size of 49 looks too small to assume the transition probability. Can’t you increase the size by expanding the enrollment period? (Although it is usually not allowed in scientific researches).

7. It is presented that one patient died due to severe attack. To me, it seems that death for attack in NMOSD patients became quite rare these days. Patients with attacks treated in advanced hospitals such as yours seem not to die so frequently. Did the patient really die from an attack? Respiratory dysfunction based on myelitis?

8. Page 9: Are the values of “25.49”, “24.29”, and “25.34” significantly different? What are the 95% CI of these values, if any? These values look only a trivial difference to me.

9. Page 10: Table 2. What is “Increment al cost”? “Al cost” does not look like an English word.

10. Page 11: “azathioprine at (30%)” does not need “at”.

11. Page 12: Title of Table 3. What is “NMOSDD”?

12. Page 14: “which reflects the natural history of NMOSD (27)”. I think the manuscript is published more about 20 years before, which is far before the discovery of serum anti-AQP4 antibody. Although you need not to remove the reference, is the “die during attacks” really a natural history in NMOSD?

13. Page 15: A recently published manuscript reported that NMOSD patients may show uneven distribution of attack occurrence (PMID: 31757816). Does this new insight possibly affect your model or future research perspective? Or such attack occurrence unevenness does not affect your conclusions? I want to read a discussion about the possible effect of such attack unevenness from your medical-economic viewpoint, if possible.

14. Page 16. “Furthermore, our estimation … very low incidence in the patient population” Although it is true that initial attack account for only a small proportion, initial attack occurrence could affect the clinical course or prognosis in NMOSD. Usually, the initial treatment is likely to be continued for the moment unless the patients experience repeated severe attacks. Thus, therapeutic strategy for newly diagnosed NMOSD patients seems to be also important. I recommend the authors to include the newly diagnosed NMOSD patients in their future researches.

15. Figure 1. This figure that shows the used Markov model should be drawn more decently. It looks like a mere sketch illustration made by PowerPoint.

16. Figure 2. Most readers may be unable to interpret this figure. What do the X-axis and Y-axis clinically imply? To which axis or dimension does the description of "More effective, less costly" belong? Lower-right side?

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2020 Feb 12;15(2):e0229028. doi: 10.1371/journal.pone.0229028.r002

Author response to Decision Letter 0

2 Jan 2020

Reviewer1

Major points:

The actual administration of rituximab in our model is “induction via intravenous rituximab at 1000 mg two weeks apart followed by 1000 mg every six months.” We have fixed this mistake in page 4 of the manuscript.

The cohort of 36 patients are included in the cost variable evaluation because these data already existed retrospectively. We used another cohort of 49 patients, instead of the 36 patients in the previous study in order to determine the transition probability because data from the 49 patients were collected in prospective manner which will be more realistic for the incidence of relapse, proportion of severe relapse, and death due to NMOSD. We added these data and included the demographic information of the second cohort in the manuscript. We included a statement to this effect on page 6 and 8 of the manuscript.

The definition of severe relapse was added in the manuscript on page 5, “Patients with severe relapse, which is defined by severe disability that was sustained or worsened after high dose steroids as indicated by Expanded Disability Status Scale (EDSS) scores ≥7.0 in patients who presented with myelitis or a visual acuity worse than 20/200 in patients who presented with optic neuritis”. We used the same definition in this study for direct medical and nonmedical costs. We have included this statement on page 5 of the paper

We have replaced the figures and added acronyms in figure legends.

Minor points:

This has been done.

2. Introduction: MMF and NLEM were never cited “in extensor” before the acronym

We have fixed this error.

3. Introduction: “Not only for the number of relapse but also the relapse severity”. Consider reword the sentence (it has no verbal predicate).

This has been done.

4. In order to favour the comprehension of the work also among Europeans and Americans, I would add the conversion of Thai Bath in Western currency (i.e. euros or dollars).

USD currency values were added in the manuscript.

5. Cost variables: “The indirect costs not include in the study to avoid double counting”. Please reword the sentence (what do you mean? That indirect costs was not included?).

This study did not include the indirect cost for analysis, following the HTA guideline of Thailand. The Indirect cost, such as the opportunity costs of patient and caregivers are not included in the study because these data have already been considered in the utility and QALY of patients. This data was referenced according to the “Avoiding Double-Counting in Pharmacoeconomic Studies” article in Pharmacoeconomics 1997 May; 11 (5): 385-388.

6. Table 3: NMOSDD should be changed in NMOSD.

This was a typing error. We have fixed this mistake.

7. Discussion: “Although the burden of NMOSD was known and recognized disease more than decate in Thailand.” Consider to write a new sentence, this lacks predicates.

We changed this to, “The burden of NMOSD was recognized more than decade ago in Thailand since NMO-IgG test was available”

8. Discussion: I would change “policy makers” into politicians.

We have done this.

Reviewer2

Major comments

1. The English throughout the manuscript is not well written. There are many grammatical errors. I strongly recommend the authors to undergo a native check.

This manuscript was sent for professional editing by Editage after we completed revisions.

You are correct. There is a study that showed steroids are effective in preventing NMOSD relapse (PMID 17623727). However, the sample size in the study was small (n = 11), and there was no RCT or systematic review. It is generally accepted that azathioprine is more effective and has less side effects. In our country, patients are typically administered azathioprine with or without steroids for relapse prevention, therefore we do not have data of PSL only.

3. What kind of statistical software did you utilize for this study? Matlab or SPSS? Please clarify in the manuscript.

All data were collected and analyzed using Microsoft Excel 2016 (License number QY49T 8WCQ7 433XX HPBCM 6DQDV). We have added this statement to the Material and Methods section, page 4.

In Western countries, rituximab is considered as the first line therapy to prevent relapse or for use as a rescue therapy after failing another first line therapy. Although there is still no consensus, patients with NMOSD in that region often have to access highly efficacious drugs for relapse prevention, without considering the cost effectiveness in NMOSD patients. This is a very different situation from low-middle income countries. Patients who suffer from failure of first line medication still have to continue with the same therapy due to inaccessible to high cost drugs. Unfortunately, patients are often ultimately disabled given the inadequate relapse prevention.

This data was added to the Discussion section of the manuscript on page 14.

5. Where are the legends for figures and tables? Please spell out the abbreviations in the figures and tables.

The figure legends were inserted after figure titles in the manuscript.

Minor comments:

1. Page 4: “rituximab (1gm)” is to be changed to “(1mg)”?

The actual dose of rituximab is 1gm. We adjusted this to 1000 mg for clarity.

We use EDSS 5.5 because an EDSS greater than 6.0 is considered a severe disability.

We agree with you. To use several clinical relapse phenotype would increase the accuracy of our model. However the visual acuity measurement is also included in the EDSS functional score even that it is not sensitive enough to show the difference after converting to EDSS. And the majority of our patients were myelitis that can be captured by EDSS change. The EDSS is also the standard measurement in most publication, so we decided to use EDSS as the measurement for all clinical attack phenotypes. None of our patients had CVO symptoms alone, they also had either myelitis or optic neuritis as the major clinical relapses which need more aggressive therapy apart from steroid alone.

4. Page 6: Were all enrolled NMOSD patients positive for the serum anti-AQP4 antibody?

Were they also screened for serum anti-MOG antibody?

Not all patients were positive for AQP4 antibody. In total, 87% of patients in the plasma exchange cohort were AQP4 seropositive (36 patients). The prospective cohort was 100% AQP4 seropositive. We added this information to the manuscript. There was no data on MOG antibody status in either cohort because the test was not available at that time.

5. Page 6: As to the cost, did you take the cost of regularly monitoring CD27+ memory B cells? Is it easily monitored in all tertiary hospitals without paying extra fee in your country?

Yes, we accounted for the cost of regularly monitoring CD27+ memory B cells in the model.

Yes, we agree that 49 patients may not provide high power to assume the transition probability. However these are the data that we can collect prospectively during that period of time.

This patients did not die after an acute attack. After the high cervical cord lesion as a consequence of severe relapse, she became ventilator dependent and developed ventilator-associated pneumonia and death due to sepsis. So we consider this death due to severe relapse.

8. Page 9: Are the values of “25.49”, “24.29”, and “25.34” significantly different? What are the 95% CI of these values, if any? These values look only a trivial difference to me.

These values in the table are life years (LYs) and were not used to compare each other. The LYs were used to calculate ICERs, which are the final outcome of our study. Since Lys and ICER were not used to compare for the statistically significant difference, so the 95% CI of these values cannot be calculated.

9. Page 10: Table 2. What is “Increment al cost”? “Al cost” does not look like an English word.

This is typing error. We have corrected it.

10. Page 11: “azathioprine at (30%)” does not need “at”.

This is typing error. We have corrected it.

11. Page 12: Title of Table 3. What is “NMOSDD”?

This is typing error. We have corrected it.

We agree that death due to a NMOSD relapse is rare given the current treatment. However, some patients who have ongoing relapse due to “unsuitable relapse prevention” is not uncommon. Severe relapse leads to an accumulation of ailments, which may cause complications, such as pressure sores, UTI, pneumonia, and sepsis leading to death or disability.

We added the following information to the manuscript on page 16-17. “Recent published data classified patients with NMOSD as clustered and nonclustered relapse, according to occurrences of relapse within 12 months from their previous attack (30). In patients with clustered relapse, the high efficacy of medication should be considered because of the frequent relapses, whereas in the nonclustered group, the relapse was infrequent. This data shows that it is possible to decrease preventive medication in order to lower costs during the nonclustered period. If we considered this strategy in our model, the cost of medication would be lower and there would be a cost savings in the cost effective analysis”.

We agree with you and will include the newly diagnosed NMOSD patient in future research.

15. Figure 1. This figure that shows the used Markov model should be drawn more decently. It looks like a mere sketch illustration made by PowerPoint.

This has been fixed.

Figure 2 is a cost effective plane study. The X-axis is Incremental QALYs (years) and Y-axis is Incremental cost (THB). We added a dialogue box of effectiveness and cost in all of the 4 Quadrant for clarity.

PLoS One. doi: 10.1371/journal.pone.0229028.r003

Decision Letter 1

Massimo Filippi

8 Jan 2020

PONE-D-19-28259R1

Cost-effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand:Economic evaluation and budget impact analysis

PLOS ONE

Dear Dr. Aungsumart,

We would appreciate receiving your revised manuscript by Feb 22 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Authors adequately replied to the points of the previous revision.

I have only few considerations (see below). Moreover, I highly recommend an accurate revision of English (I doubt a professional editing was performed, as, basically, no language corrections are present in the revised manuscript).

Major points:

1. Cost variables: Unfortunately, as 13% of patients are seronegative (and this population could have a different relapse-rate), Authors should at least add data regarding seronegative patients (do the ARR and disease severity differ from seropositive patients?). As the longitudinal population includes seropositive patients only, this should be taken into account in the statistical analysis or this point should at least be discussed.

Minor points:

1. THB and USD are not spelled out in the Abstract section.

2. Introduction: “NMOSD is a devastating CNS inflammatory demyelination”. Please, prefer “NMOSD is a devastating CNS inflammatory demyelinating disease”.

3. Material and methods: “Which began induction via intravenous rituximab [...]”. Please, revise the syntax of this sentence.

4. Material and methods: USD is not spelled out. Moreover, I would move the exchange rate sentence to the beginning of the “Cost variables” section.

5. Clinical variables: I thank the Authors for adding the clinical and demographic features of the longitudinal NMOSD cohort, but please, revise the English.

6. Please, add USD to Table 2, Table 3 and page 16.

7. “The burden of NMOSD was recognized more than decade in Thailand”. Please, revise the English.

8. Discussion: “[…] inaccessible to high cost drugs. Unfortunately […]”. Please, consider revising (i.e., “[…] inaccessible to high cost drugs with consequent inadequate relapse prevention and disability accrual.”)

9. Discussion: “[…] which helped represent […]”. Consider revising (i.e. “[…] which helped representing […]”).

10. Please correct “these parameters was analysed” in “were analysed”.

Reviewer #2: I think that the authors appropriately responded to the comments and concerns raised from my part. I feel that the revised manuscript has been much improved from the original one.

**********

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Reviewer #1: No

Reviewer #2: No

PLoS One. 2020 Feb 12;15(2):e0229028. doi: 10.1371/journal.pone.0229028.r004

Author response to Decision Letter 1

22 Jan 2020

Reviewer #1: Authors adequately replied to the points of the previous revision.

Major points:

Answer: We have added the demographic data of the seronegative patients to page 7 of the manuscript. Moreover, this point was added to the discussion section on page 18: “In other words, cost parameters generated by patient groups of mixed populations of seronegative NMOSD who exhibited lower relapse rates will lower the cost parameters more than expected. Those patients in the seropositive NMOSD group who more frequently relapse will incur higher costs for both direct and indirect medical expenses compared with the seronegative patients. However, if we apply only AQP4 positive NMOSD in the cost calculations, using high efficacy medication will result in greater differences in reducing relapse frequency and in further reducing the costs associated with treatments. Hence, the ICER that generates this situation negatively impacts our results, which indicates greater cost savings when treating NMOSD with high efficacy medications”.

Minor points:

1. THB and USD are not spelled out in the Abstract section.

This has been done.

2. Introduction: “NMOSD is a devastating CNS inflammatory demyelination”. Please, prefer “NMOSD is a devastating CNS inflammatory demyelinating disease”.

This has been done.

3. Material and methods: “Which began induction via intravenous rituximab [...]”. Please, revise the syntax of this sentence.

This sentence was revised to read, “which began with the introduction of two 1000 mg intravenous rituximab doses two weeks apart followed by 1000 mg intravenous rituximab doses every six months.”

4. Material and methods: USD is not spelled out. Moreover, I would move the exchange rate sentence to the beginning of the “Cost variables” section.

This has been done.

5. Clinical variables: I thank the Authors for adding the clinical and demographic features of the longitudinal NMOSD cohort, but please, revise the English.

This manuscript was sent to a new company (Elsevier language editing company) for English language editing after we completed the revisions. The certificate is attached to this revision.

6. Please, add USD to Table 2, Table 3 and page 16.

This has been done.

7. “The burden of NMOSD was recognized more than decade in Thailand”. Please, revise the English.

This sentence was revised as follows: “The issues with respect to NMOSD have been acknowledged for more than a decade in Thailand, i.e., since the NMO-IgG test had been made available…”

This has been done.

9. Discussion: “[…] which helped represent […]”. Consider revising (i.e. “[…] which helped representing […]”).

This has been done.

10. Please correct “these parameters was analysed” in “were analysed”.

This has been done.

Attachment

Submitted filename: Rebuttal for Reviewer1 22-01-2020.docx

Click here for additional data file.^{(15.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0229028.r005

Decision Letter 2

Massimo Filippi

29 Jan 2020

Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand Economic evaluation and budget impact analysis

PONE-D-19-28259R2

Dear Dr. Aungsumart,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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PLoS One. doi: 10.1371/journal.pone.0229028.r006

Acceptance letter

Massimo Filippi

5 Feb 2020

PONE-D-19-28259R2

Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand: Economic evaluation and budget impact analysis

Dear Dr. Aungsumart:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Meta-analysis of mycophenolate mofetil in comparison to azathioprine in relapse-free NMOSD.

(TIF)

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S2 Fig. Cost-effectiveness plane.

(TIF)

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S3 Fig. Cost-effectiveness acceptability curves.

(TIF)

Click here for additional data file.^{(568.7KB, tif)}

S1 Text. Treatment efficacy of MMF.

(DOCX)

Click here for additional data file.^{(63.8KB, docx)}

Attachment

Submitted filename: Rebuttal for Reviewer1 22-01-2020.docx

Click here for additional data file.^{(15.6KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand: Economic evaluation and budget impact analysis

Saharat Aungsumart

Metha Apiwattanakul

Roles

Abstract

Introduction

Materials and methods

Economic model

Fig 1. Schematic Markov model for neuromyelitis optica spectrum disorder (NMOSD) treatment.

Cost variables

Clinical variables

Health outcomes

Table 1. Cost and input parameters of decision models.

Uncertainty analysis

Budget impact analysis

Institution review board

Results

Cost-utility analysis

Table 2. Costs and outcomes for each medication are expressed in THB (USD).

Fig 2. Cost-effectiveness plane of lifetime cost and effectiveness of six treatment options for NMOSD.

Uncertainty analysis

Fig 3. Acceptability curves of the cost effectiveness at different ceiling thresholds for six NMOSD treatment options.

Fig 4. Results of a one-way sensitivity analysis of the administration of a rituximab biosimilar with a CD27+ B cells monitoring regimen compared to that of azathioprine in the treatment of NMOSD patients.

Sensitivity analysis based on the current price reduction for MMF

Budget impact analysis

Table 3. Budget impact of the adoption of new therapies for NMOSD in THB (USD).

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Massimo Filippi

Roles

Author response to Decision Letter 0

Decision Letter 1

Massimo Filippi

Roles

Author response to Decision Letter 1

Decision Letter 2

Massimo Filippi

Roles

Acceptance letter

Massimo Filippi

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Fig 4. Results of a one-way sensitivity analysis of the administration of a rituximab biosimilar with a CD27⁺ B cells monitoring regimen compared to that of azathioprine in the treatment of NMOSD patients.