Abstract
Introduction:
In order to estimate the value of interventions in multiple sclerosis (MS) – where lifetime costs and outcomes cannot be observed – outcome data have to be combined with costs. This requires that cost data be regularly updated.
Objectives and methods:
This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, in the societal perspective, in CZK 2015.
Results:
A total of 747 patients (mean age 47 years) participated; 86% were below retirement age and of these, 49% were employed. Employment was related to disease severity, and MS affected productivity at work for 82% of those working. Overall, 92% and 66% of patients experienced fatigue and cognitive difficulties as a problem. Mean utility and annual costs were 0.832 and 257,000CZK at Expanded Disability Status Scale (EDSS) 0–3, 0.530 and 425,500CZK at EDSS 4–6.5 and 0.141 and 489,000CZK at EDSS 7–9. The average cost of a relapse was estimated at 12,600CZK.
Conclusion:
This study provides current data on MS in the Czech Republic that are important for the development of health policies.
Introduction
The availability of disease-modifying treatments (DMTs) in multiple sclerosis (MS) has led to changes in patient management and a focus on earlier and better diagnosis and adjustments in the diagnostic criteria themselves. One of the consequences in this regard is that the recorded prevalence of the disease is quite different from that estimated two or three decades ago,1,2 with an increase in prevalence in the Czech Republic to 170/100,000 population in 2012. 3 With diagnosis possible already after one clinically isolated event (CIS), one must also expect a larger proportion of patients in the early stages of EDSS and on treatment with DMTs. According to the Czech DMT registry (ReMuS), almost 9000 patients were treated in MS centres in 2016. 4 This has a considerable impact on healthcare budgets, and it is therefore important to have detailed information on the burden of MS, the resource utilisation associated with it, its impact on the quality of life of patients, as well as on outcomes achieved with different treatment strategies.
The Czech Republic introduced a formal health technology assessment (HTA) process in 2008, and formal cost-effectiveness studies have been integrated into the decision-making processes since 2012. Since then, the number of economic studies, both cost of illness assessments and cost-effectiveness analyses in the country, has increased as every new drug and indication is under HTA review. Specific data on the costs of MS were however lacking until more recently. In 2007, a detailed clinical and economic assessment of 909 patients was performed in a group of MS Centers, the Cost of MS in the Czech Republic (COMS) study. 5 The study used a similar methodology for the economic assessment as a European survey performed by Kobelt and colleagues6,7 in 2005 in order to allow comparison.
The study presented here is part of a renewed European-wide effort in 16 countries to investigate the burden of MS, 8 using a similar methodology as the European survey in 2005. 6 The study was endorsed by the European Platform of MS Societies (EMSP) and carried out with the support of national MS societies. 8
Materials and methods
The detailed methodology of the European survey is published separately. 7 We therefore only provide a short summary of the general methods and issues specific to the Czech Republic.
Data
The study aimed to estimate the costs of all healthcare and other resource utilisation related to MS: hospitalisation, rehabilitation, consultations, diagnostic procedures and tests, medication, community care, family support and production losses (sick leave, early retirement, invalidity). In addition, information on major symptoms such as fatigue and cognitive difficulties (using visual analogue scales (VAS)), health-related quality of life (HRQoL) and utility (using the EuroQol-5D (EQ-5D) 9 ), as well as patient-assessed disability using descriptions based on the Expanded Disability Status Scale (EDSS), was collected.
Data were collected with a standard questionnaire, at a single point in time, for a retrospective period of time. The latter was varied depending on the question in order to minimise recall bias: 1 month for use of drugs, community services and family help; 3 months for hospitalisation, consultations, tests, sick leave and relapses; and 12 months for major investments. Resource utilisation is reported for these time periods, while cost calculations are annualised.
Disease information such as the type of MS, disability, HRQoL, utility, symptoms (fatigue, cognitive difficulties) and the effect of MS on work related to the current day or week. For comparability across countries, 10 utilities were estimated with the original value set developed for the EQ-5D in the United Kingdom. 11 Also, contrary to many other European countries, no specific value set for the Czech Republic is available to date.
The handling of missing data for the cost calculation is explained in more detail in the paper describing the methods. 7 For resource use, we present actual answers without any imputation for missing answers. Also, no imputations are made for missing information on disease status, symptoms and HRQoL.
Costs
Costs are calculated from the societal perspective, including all costs regardless of who ultimately is responsible for them. Patient co-payments and patients’ out-of-pocket expenses are thus included. The cost of a relapse is calculated as the difference in quarterly costs between patients with or without a relapse and an EDSS score <6, with the hypothesis that relapses were seldom longer than 3 months and were less frequent at higher EDSS levels. Costs that are unlikely to be affected within 3 months (invalidity, early retirement and DMT treatment) were excluded. This calculation was only based on patients who answered yes or no to the question about relapses; patients who were unsure about it were excluded.
Unit costs for the individual resources were taken from public sources (summarised in the description of the study methods 7 ), and results are reported in Czech Koruna (CZK 2015; 1€ = 27.022CZK average exchange rate 2015).
Patients
The objective was to include a sample where all levels of disease severity (defined by EDSS) were represented in sufficient numbers to permit analysis, rather than a prevalence sample. This highlights how costs and HRQoL change as the disease progresses and provides the necessary data for cost-effectiveness analysis of treatments that are expected to change the course of the disease. Mean results may thus not be representative and should neither be extrapolated directly to national costs nor be compared directly to the results in earlier studies. We therefore report results by disease severity groups only (mild disability EDSS 0–3, moderate disability EDSS 4–6.5 and severe disability EDSS 7–9).
Data collection
In anonymous surveys, it is difficult to include a fully representative patient population, and changes in management, in particular early diagnosis, have increased this challenge. In addition, participation will depend heavily on the methods used for the survey: collecting data in MS centres tends to overestimate the number of patients with early but severe disease and on treatment with DMTs, and collecting data from members in patient organisations may lead to the opposite. Internet surveys will bias towards younger patients with better education, while postal mailing may bias towards older patients.
In the Czech Republic, participants came both from the Czech MS Society (Unie Roska) and from the clinical centres. The data were collected during the winter 2015/2016, after approval by the Ethical Committee of the General University Hospital in Prague. The MS society distributed the survey to 750 members by e-mail. A number of clinical centres that had participated in the COMS study contacted participants in COMS by e-mail and/or telephone, as their identities were known to the centres. To preserve anonymity in the international survey, all identities were concealed in the database.
Results
A total of 747 evaluable responses were received, all online. Of these, 449 patients had participated in the COMS study. The geographical representation of the sample is thus partially influenced by the location of the clinical centres. Table 1 provides details on demographics, employment and disease.
Sample demographics.
SD: standard deviation; EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; DMTs: disease-modifying treatments.
Of total sample (N = 747).
Of patients of working age (N = 644).
Of patients working (N = 375).
Demographics and employment
The age of respondents in this sample ranged from 19 to 81 years (mean: 46.7; median: 45.0; standard deviation (SD): 12.0); women represented 75%; 83% lived with their family; and eight patients were in a nursing home at the time of the survey.
Education levels in our sample were higher than in the general population in 2015: 5% of patients had basic education, 66% had a secondary or a professional degree and 29% a university degree. This compares to 17%/69%/13% in the general population in the last national census in 2011. The main reason for the higher proportion of university degrees in MS patients is the higher share of younger women.
The majority of patients in the sample were of working age: 644 patients (86%). Of these, 367 patients (49%) were employed or self-employed. Eight patients above retirement age also worked, bringing this group to 375 patients (or 50% of the full sample). This compares to an activity rate of 74% in the whole population between 15 and 64 years in 2016. The comparison with data in the ReMuS registry reveals a much higher proportion of patients working when on DMT therapy (73%), that is, very close to the participation rate in the population (74%). The mean age in the employed group was 42.2 (SD: 9.3) years. The majority worked part-time (91%), and of these, 61% did so because of MS. This compares to a level of part-time work in the population of 5.5% (9.5% for women). Average working hours in the sample were 41.0 hours for full-time workers, 21.8 hours for part-time employment and 27.5 hours for part-time employment due to MS. Sick leave during the past 3 months was reported by 22 patients (6%), with a mean duration of 24.2 days.
Employment decreased rapidly with advancing disease, as shown in Figure 1. Of non-employed patients of working age, 34% indicated MS as the reason. Within the full sample, 31% indicated having left the workforce due to MS.
Employment by disease severity.
Most employed patients felt that MS affected their productivity at work (67%); 17% indicated that they had no problems, while 16% had not answered the question. The severity of the effect covered the entire VAS range from 0 to 10, with a mean of 2.7 (SD: 2.5) (Figure 2). Fatigue was considered the most bothersome symptom (74%), followed by mobility (27%), low mood (22%), difficulty thinking (16%) and pain (16%).
Fatigue, cognitive difficulties and effect of MS on productivity at work.
Disease information
Disease information is summarised in Table 1. The mean EDSS in the sample was 3.5 (SD: 2.7). With the exception of the most severe level (EDSS 9, 14 patients), all levels reached the target of 50 patients. For our analysis, the mild group (EDSS 0–3) represented 52% of the sample, the moderate group (EDSS 4–6.5) 33% and the severe group (EDSS 7–9) 15%; no EDSS data were missing. This distribution corresponds rather well to what is currently expected 5 and indicates that our sample is representative.
The proportion of patients with relapsing-remitting multiple sclerosis (RRMS) disease was 58%, with secondary progressive multiple sclerosis (SPMS) disease 21% and with primary progressive multiple sclerosis (PPMS) disease 19%. This latter proportion is higher than what is expected, 1 with the same finding in the COMS study (8%) 5 and attests to the difficulty for patients to judge the type of disease. We therefore ignore the disease type in our analyses and focus instead on EDSS levels. DMTs were used by 54% of the sample, with usage lower in the high EDSS levels as expected, particularly as reimbursement coverage ceases above EDSS 6.5 (Table 1). Among users, 26% were on their first DMT treatment, and first-generation DMTs were used by 65% (Table 2).
Type of DMTs used (N = 405).
DMT: disease-modifying treatment.
Relapses in the preceding 3 months were reported by 124 patients (17%) and happened at all stages of the disease (Table 1). However, 152 patients (20%) were unsure whether they had a relapse or not, and we assumed that the answer was no. Thus, the mean relapse rate over a 3-month period was estimated at 0.3 (SD: 0.7). Corticosteroids were given to two-thirds of patients with relapses, most often intravenously.
Symptoms and HRQoL
Fatigue and cognitive difficulties were an issue for the majority of patients, and both were related to disease severity (Figure 2). Fatigue was present in 92% of patients who answered the VAS (3% missing). The mean score was 5.0 (SD: 2.7) for the sample, 3.8 for patients with mild diseases, 6.2 for patients in the moderate group and 6.3 in the severe group. Cognitive difficulties were recognised by 53% of patients. The mean VAS score in this group with difficulties was 3.9 (SD: 2.0) overall, 3.3 in the mild, 4.2 in the moderate and 4.6 in the severe group. For the total study sample, assigning 0 to the group with no problems, the mean score was 2.0 (SD: 2.4), and 1.5, 2.8 and 2.3 in the three groups, respectively.
All five domains of HRQoL included in the EQ-5D 9 displayed problems for a large proportion of patients: mobility for 63%, pain/discomfort for 60%, usual activities for 56%, anxiety/depression for 52% and self care for 32%. Both the severity and the domains most affected changed with advancing disease. Self-care was unaffected in the early stages of disability, but problems increased rapidly with basically no patient unaffected in severe disease. All other domains presented problems already in early disease with more difficulties experienced with increasing EDSS. Problems with anxiety and depression were present at all stages of EDSS (Figure 3).
Problems in different domains of QoL (EQ-5D), N = 747.
Utility
Utility declined with increasing EDSS (Figure 4). Values decrease to negative values in severe disease, with a mean in this sample estimated at 0.629 (SD: 0.334).
Utility by EDSS (N = 747).
Resource utilisation
Resource utilisation is presented in Table 3. Inpatient admissions during the preceding 3 months occurred for only 22 patients (3%); 14 patients (2%) were admitted to the neurology ward, on average 1.4 times (SD: 0.9), and for a mean of 5.6 days (SD: 4.8), indicating a small group of patients with particularly severe and active disease. A total of 32 patients (4%) had day admissions, most often to the neurology ward (30 patients), on average once a month (mean: 3.2; SD: 2.4). This may be related to administration of treatment (monthly injections and infusions). Inpatient or day admissions to rehabilitation centres were required by 87 patients (12%).
Resource utilisation, health care and community services.
MS: multiple sclerosis; SD: standard deviation; MRI: magnetic resonance imaging; DMT: disease-modifying treatment; OTC: over the counter drugs.
The majority of patients had at least one consultation during the past 3 months (470 patients, 63%), most often with a neurologist (409 patients), a general practitioner (122 patients) or a physiotherapist (73 patients). A third of patients underwent investigations and tests (247 patients, 33%) and medication was used by 81% of patients during the past month. Prescription drugs other than DMTs and corticosteroids were used by 171 patients (23%), predominantly treatments for walking, spasticity and pain and for depression (Table 3). Over the counter drugs were used by 430 patients (58%).
Investments in equipment and devices to aid patients’ mobility were made during the past 12 months for or by 169 patients (23%), most often for walking aids and modifications to the car or the house.
Community and social services were used by only 9% of patients, pointing towards a lack of availability of such services. Help from the family was used by 41% of patients, on average 17.2 days/month and 5.6 hours/day. Both community services and informal care were related to disease severity (Figure 5).
The use of informal care (days per month and hours per day, per user).
Costs
Total mean annual costs per patient for patients with mild, moderate and severe disease and by EDSS score are presented in Figure 6 and Table 4.
Total mean annual cost per patient by disease severity (N = 747).
Total mean annual cost per patient by disease severity (mild, moderate and severe), N = 747 (CZK 2015).
CZK: Czech Koruna; EDSS: Expanded Disability Status Scale; DMTs: disease-modifying treatment.
The average cost of relapses for patients with an EDSS up to 6 was estimated at 12,600CZK (excluding DMTs, invalidity and early retirement), with all resources increasing during a relapse. For comparison, for COMS patients, 5 the cost of a relapse was estimated at 4500CZK in mild MS, 21,600CZK in moderate MS and 37,000CZK in severe MS (T. Dolezal, personal communication) (Figure 7).
Relapse costs (3 months).
Discussion
The aim of this study was to estimate the current economic and health burden of MS in the Czech Republic and to assess the impact of fatigue and cognitive symptoms on daily living.
Our results are very consistent with findings in other studies, including the COMS study. Costs double as the disease becomes severe, while utility reaches values considered worse than death.
Up to and including EDSS 5, the vast majority of costs results from DMT use, although these might be slightly overestimated. We have used public list prices in our analysis, as discounts are not publicly available. It is estimated that the final selling price to payers in the Czech Republic is 15%–20% lower than the list prices. However, even using discounted prices, DMTs would dominate costs in early disease. The high treatment rate in early disease is representative of management of MS in the Czech Republic with good access to the older drugs (interferons and glatiramer acetate). However, the switch to newer and more expensive drugs is slow due to financial pressures.
Starting at EDSS 6, production losses and informal care represent around half of the cost. Costs for community services are low, except at the most severe level (EDSS 9), indicating that these services are not readily available to the majority of patients.
Half the patients in our study are still working after an average of 15 years since diagnosis. This is consistent with international studies, but cross-sectional studies do not allow investigation of the causes or reasons. Nevertheless, the most recent analysis of the data in the Czech MS registry (ReMuS) 12 suggests that working ability may be dependent on the availability of DMT therapy, as 73% of patients on DMT treatment are working 10 years after diagnosis. It is not possible to compare our findings directly to these data, as the mean EDSS in ReMuS in 2016 was lower than in our study (2.6 versus 3.5). This may result from a selection of patients in ReMuS, as in the Czech Republic patients are eligible for treatment after a CIS and ReMus will thus have more patients with early disease than the prevalence in the population.
The pattern of utilities, decreasing with disability progression, is similar to the other countries in this study series and to findings in COMS.5,10
Our results point towards the importance of starting effective DMT treatment early with stepwise escalation as needed, both from a clinical and a health economic perspective. 13 Although no causality can be shown in this study, ReMuS has shown that production losses are low in patients with early active MS and effective DMT therapy. 4 The challenge remains, however, to show how production losses and informal care – that is, costs outside the healthcare system – are better controlled by delaying disability progression.
Footnotes
Acknowledgements
The authors are grateful to Jana Hlavácová (SMS) and Eva Skobisova (Roska) for making the survey available to members, to Miluse Pavelcova (Neurology Department, Charles University) for contacting individual participants of the COMS study, to Jennifer Eriksson and Johan Dalén (MAPI Group) for organisational and statistical support, to Markas Gedminas (Medscinet) for construction of the online platform, to Barbara Rosengren for language editing and to Cara Harley for formatting.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.H. has received consulting fees from Actelion, Biogen, Celgene, Merck Serono, Novartis, Sanofi Genzyme, Roche and Teva, as well as support for research activities from Czech Ministry of Education project PROGRES Q27/LF1. G.K. has received consulting fees from Almirall, Bayer, Biogen, Merck Serono, Novartis, Oxford PharmaGenesis, Sanofi Genzyme and Teva. J.B., D.C., M.G. were at the time of the study employed by the MAPI Group, a research company acting as consultants to pharmaceutical companies. T.D. was at the time of the study owner of VALUE outcomes, a contract research company acting as consultants to pharmaceutical companies.
Funding
The author(s) declared receipt of the following financial support for the research, authorship and/or publication of this article: European Health Economics and MAPI have received funding for the full research and production of the manuscripts from Biogen.