Abstract
Introduction:
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 EUR 2015.
Results:
A total of 491 patients (mean age 47 years) participated; 82% were below retirement age, and of these 56% were employed. Employment was related to disease severity, and MS affected productivity at work for 90% of patients. Overall, 95% and 67% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.735 and €22,600 at Expanded Disability Status Scale (EDSS) 0–3, 0.500 and €38,100 at EDSS 4–6.5, and 0.337 and €48,100 at EDSS 7–9, respectively. The average cost of a relapse was estimated at €2300.
Conclusion:
This study provides current data on MS in France that are important for developments of health policies and to estimate the value of current and future treatments.
Introduction
Cost-effectiveness studies have been integrated into the decision-making processes in France only recently. In 2008, the Finance Act introduced health economic evaluation into the French market access process, through the creation of the Commission for Economic Evaluation and Public Health (CEESP). 1 The act’s goal was to ensure optimisation of healthcare resources. The Social Security Finance Act of 2012 further defined the role of the CEESP to assess health economic data supplied by manufacturers for new treatments expected to have major, important or moderate medical benefit (amélioration du service médical rendu (ASMR) I to III) and/or a significant impact (⩾20 million €) on the health insurance budget. 2 At the same time, the CEESP issued methodological guidelines for performing economic evaluation in France. 3 Assessments by the CEESP thus form part of the basis for decision-making by the Pricing Committee (CEPS, part of the Ministries of Health and Economics) since only 2012.
Due to this late official integration of health economic data into the decision-making process, and consequently a lack of interest in economic studies in healthcare, the number of economic studies performed in France is limited compared to other countries. Such studies are most often done when a new product enters the market and reimbursement is sought. Despite this, French cost of illness data for multiple sclerosis (MS) has been published alongside international efforts in the past two decades.4–7
The availability of disease-modifying treatments (DMTs) 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, leading to an increase in prevalence to 135/100,000 population in 2015.8–10 With diagnosis possible already after one clinically isolated event, 11 one must also expect a larger proportion of patients in the early stages of the disease and with less disability, and on treatment with DMTs. This has a considerable impact on healthcare budgets, and the challenge will increase further as new products allow extension of treatment to the more advanced stages of MS. It will be important to weigh outcomes against costs.
It is therefore important to update the information on the burden of MS, and the study presented here is part of a European-wide effort in 16 countries, endorsed by the European Platform of MS Societies (EMSP) 12 and carried out with the support of national MS societies. 12 It uses a similar methodology as the last European survey in 2005 13 (France was not part of the 2005 study, but a French study was performed separately the following year 5 ).
Materials and methods
The detailed methodology for the European survey is published separately. 14 We therefore only provide a short summary of the general methods and issues specific to France.
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 cognition, using visual analogue scale (VAS), health-related quality of life (HRQoL) as well as self-assessed disability using descriptions based on the Expanded Disability Status Scale (EDSS) were 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 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; 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 (EDSS), HRQoL, utility (EuroQol five dimensions (EQ-5D)), 15 symptoms (fatigue, cognition) and the effect of MS on work related to the current week. For comparability across countries, 12 utilities are estimated with the original value set developed in the United Kingdom. 16 In France, a specific national value set was established more recently, 17 and we therefore also present utilities established with the local tariff.
Costs
Costs are calculated in 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 0–6, with the hypothesis that relapses were seldom longer than 3 months and were less frequent at higher EDSS levels. In addition, the number of patients above EDSS 6 was too small to provide relevant data. Resources unlikely to be directly affected during the quarter by a relapse were excluded from the calculations (invalidity, early retirement, DMTs).
Unit costs for the individual resources were taken from public sources (summarised in the description of the study methods) 14 and the results are reported in EUR (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 allows highlighting 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. The 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 the results by disease severity groups only (mild disability EDSS 0–3, moderate disability EDSS 4–6.5, severe disability EDSS 7–9).
Data collection
It is generally difficult to include a fully representative patient population in anonymous surveys. 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 18 and on treatment with DMTs; collecting data from members in patient organisations may lead to the opposite. Internet surveys will bias towards younger patients with better education. French participants in this study came from both patient organisations and 11 clinical centres, and we thus expect a certain bias towards patients with early active disease and on treatment.
The French data were collected during the first quarter of 2016, later than in most countries in the study, as approval by the ethics commission (CCTIRS) and the commission for individual liberties (CNIL) took more than 1 year. As the database for the overall study had to be closed at the end of March 2016, this left only a limited time and may explain the small sample compared to other countries.
Two patient organisations took part in the study and distributed the survey to their members: the ‘Ligue francaise contre la sclérose en plaques’ (LFSEP) and the ‘Union associative pour lutter contre la sclérose en plaques’ (UNISEP). However, response was slow, and in view of the short time frame we decided to complement the associations’ samples with consecutive patients from a number of MS clinics (N = 11). Participating clinicians were members of the French MS Society (SFSEP).
Results
A total of 491 evaluable responses were received (161 online and 330 on paper). Patients from all regions (Départements) were represented, with however slightly larger groups in those areas where SFSEP clinicians were participating.
Table 1 provides details on demographics, employment and disease.
Sample demographics and disease information.
MS: multiple sclerosis; EDSS: Expanded Disability Status Scale; SD: standard deviation, RRMS: relapsing-remitting multiple sclerosis; DMT: disease-modifying treatment.
Of total sample (n = 491).
Of patients of working age (N = 403).
Of patients working (N = 232).
Demographics and employment
The age of respondents in France ranged from 19 to 86 years (mean 47.2 years, median 47.0 years, standard deviation (SD) 13.1 years); women represented 74%; 77% lived with their family and no patient was in a nursing home at the time of the survey.
Education levels in our sample were higher than in the general population in 2015: 9% of patients had basic education, 37% had a secondary or a professional degree and 53% a university degree, compared to 16%, 43% and 41%, respectively, in the population aged 25–49 years, and 28%, 37% and 35%, respectively, for the total population. 19 One reason for this may be that the international questionnaire asked only for ‘university degree’ without specifying the minimum number of years or type of diplomas. It is also possible that this type of questionnaire is more easily completed by people with better education, or that patients with higher education access tertiary MS centres more easily.
The majority of patients in the sample were below effective retirement age (60 years for both women and men): 20 403 patients (82%). Of these, 226 patients (56%) patients were employed or self-employed. Six patients above retirement age also worked, bringing this group to 232 patients (or 47% of the full sample). This compares to an activity rate of 71.4% in the population between 15 and 64 years in 2014 (67.5% for women and 75.5% for men). 21 The mean age in this group was 42.2 (SD 9.8) years. The majority of patients worked part-time (78%); of these, 36% did so because of MS. This is considerably higher than in the general population where 30.6% of women and 7.2% of men work part-time, two-thirds of them less than 30 hours per week. 22 The average working hours in the sample were 42.7 hours for full-time workers and 26.1 hours for part-time employees. Sick leave during the past 3 months was reported by 22% of patients, with a mean duration of 18.4 days. Both the number of patients with sick leave and the mean duration indicate that sick leave is not exclusively related to relapses, but has other causes as well.
Employment decreased rapidly with advancing disease, as shown in Figure 1. Of non-employed patients below retirement age, 35% indicated MS as the reason.
Proportion of patients below retirement age employed or self-employed.
Most employed patients felt that MS affected their productivity at work (81%) and only 8% indicated that they had no problems, while 10% had not answered the question. The severity of the effect covered the entire range from 0 to 10, with a mean of 4.2 (SD 2.7; Figure 2) Fatigue was considered the most bothersome symptom while at work (94%), followed by difficulties thinking (40%), pain (32%), low mood (28%) and mobility (28%).
Mean score on the visual analogue scale (0 = no problem; 10 = severe problems) for fatigue, cognitive difficulties and impact of MS at work (only for patients working). Patients with missing EDSS (n = 27) or missing answers are excluded. EDSS: Expanded Disability Status Scale.
Disease information
Disease information is summarised in Table 1. The mean EDSS in the sample was 3.6 (SD 2.3, range 0–8). The number of patients at each EDSS level exceeded 30, yielding a stable analysis, except in the severe levels with only 27 and 20 patients at EDSS 7 and 8, respectively, and none at EDSS 9. This is not surprising as patients at this severe level are not in regular contact with neurologists or patient associations. Our costs estimated for the severe group of patients may thus be slightly underestimated. The mild group represented 47% of the sample, the moderate group represented 38% and the severe group 10%; EDSS data were missing for 5% of patients.
The proportion of patients with relapsing-remitting multiple sclerosis (RRMS) was 61%, and patients with secondary progressive multiple sclerosis (SPMS) represented 22% of the sample. Eleven percent of patients had primary progressive disease. This corresponds to the distribution currently seen in the French MS Observatory (Observatoire Français de la Sclérose en Plaques (OFSEP)), 57%, 22% and 10%, respectively, and can thus be considered representative. 23 However, in previous studies5,13 and in a number of countries participating in this study, it was evident that patients were uncertain in their answers regarding the type of disease. We therefore did not include the disease type in our analyses and focus instead on EDSS levels. DMTs were used by 78% of the sample, with usage declining with higher EDSS levels, as expected (Table 1). Among users, 32% were on their first DMT treatment. First-generation DMTs were used by 27%, newer DMTs by 67% and data were missing for 8% of patients (Table 2).
Type of DMTs used (N = 382 a ).
DMT: disease-modifying treatment. aMissing information on the type of DMT for 32 patients.
Relapses in the preceding 3 months were reported by 72 patients (15%) of which 58% occurred in the past month (Table 1). However, 82 patients (17%) were unsure whether they had a relapse or not, and 10 patients (2%) did not answer. For these two groups, we assumed that the answer was no. Thus, the mean relapse rate over a 3-month period was estimated at 0.2 (SD 0.5). Corticosteroids were used by 86% of all patients with relapses, or 12% of the total sample.
Symptoms and HRQoL
Fatigue and cognitive difficulties were an issue for a majority of patients, and both were related to disease severity (Figure 2). Fatigue was present in 95% of patients. The mean score was 5.7 (SD 2.3) for the sample, 5.2 for patients with mild diseases, 6.2 for patients in the moderate group and 6.7 in the severe group. Cognitive difficulties were recognised by 67% of patients. The mean VAS score in this group was 4.7 (SD 2.0) overall, 4.3 in the mild, 4.9 in the moderate and 5.7 in the severe group. For the full study sample (assigning 0 to the group with no problems), the mean score was 3.3 (2.6, 3.9 and 4.2).
Among the five domains of HRQoL included in the EQ-5D, only self-care did not represent problems for a majority of patients. Both the severity and the type of domain affected changed with advancing disease (Figure 3).
Proportions of patients at different levels of disease severity experiencing difficulties in the five domains of the EQ-5D (EuroQol five dimensions). The ability for self-care remains least affected until severe disease, while all other domains become difficult rapidly as the disease progresses. Pain and anxiety are present early and appear more severe in the mild group.
Utility
Utility decreased with increasing EDSS using both the UK and the French value sets (Figure 4).16,17 The mean utility in the sample was 0.616 and 0.583 using the UK and French tariffs, respectively. The two curves are rather similar, although the French curve is slightly steeper: Utilities estimated with the French value set were higher than utilities with the UK value set in mild disease but lower for severe disease.
Utility by EDSS level estimated with the UK and French value sets of the EQ-5D established with the general population.16,17 Utility is calculated by relating the scores (1 = no problem; 2 = some problems; 3 = severe problems) of the five domains to a health state valuation system established with the general population using decision analytic methods. The results are very similar, although the French population appears to rate the severe health states more negatively. EDSS: Expanded Disability Status Scale.
Resource utilisation
Resource utilisation is presented in Table 3. During the preceding 3 months, 41 patients (8%) were admitted as inpatients, most often in a neurology ward (31 patients), on average twice and for a mean of 5.3 days (Table 3). More than a third of patients (177 or 36%) had day admissions, on average once a month (mean 2.9, SD 3.0). This illustrates the French practice until recently of admitting patients for treatment (monthly injections and infusions). Most of these day admissions happened in the neurology ward (82%). Inpatient or day admissions to rehabilitation centres occurred for 50 patients (10.2%)
Resource utilisation, healthcare and community services.
SD: standard deviation; MS: multiple sclerosis; MRI: magnetic resonance imaging; DMT: disease-modifying treatment; OTC: over the counter drugs.
The majority of patients (401, 82%) had a consultation during the past 3 months, most often with a neurologist (301 patients), a general practitioner (190 patients) or a physiotherapist (200 patients). Two-thirds underwent investigations and tests (326 patients, 66%), and medication was used by 94% of patients during the past month. Drugs other than DMTs were used by 230 patients (47%), predominantly treatments for walking, spasticity and pain (158 patients, 32%) and for depression (79 patients, 16%). In the group with a relapse (72 patients), oral corticosteroids were used by 17 patients, while 48 patients were treated with infusions.
Investments in equipment and devices to aid patients’ mobility were made during the past 12 months for or by 138 patients (28%), most often for walking aids, wheel chairs and modifications to the car or the house.
Community and social services were used by 26% of patients, most frequently home help and transportation. Help from family was used by 40% of patients, on average 16.7 days per month and 3.7 hours per day. Both community services and informal care were related to disease severity (Figure 5).
Intensity of use of informal care (number of days and hours per day during the past month). Use is concentrated in the severe group: 17% of patients in the mild, 54% in the moderate and 94% in the severe group are relying on family support.
Costs
The 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.
Mean total annual costs per patient by level of EDSS. Total costs increase with disease severity, but the types of resources change. Healthcare costs dominate in early disease, production losses, community services and informal care in more severe disease.
Total mean annual cost per patient by disease severity (mild, moderate, severe), N = 491 (EUR 2015).
EDSS: Expanded Disability Status Scale; SD: standard deviation; DMT: disease-modifying treatment.
The average cost of relapses for patients with an EDSS up to 6 was estimated at €2305. All types of resources increased, with sick leaves representing 21% and inpatient care and day admissions 18% each (Figure 7).
Mean total 3-month costs for patients below EDSS 6.5 with and without a relapse. The cost of a relapse is calculated as the difference between the two groups, excluding DMTs, invalidity pensions and early retirement (€2305) Use of all resources increases for patients with a relapse, but the largest difference arises from sick leave and inpatient and day admissions.
Discussion
The aim of this study was to update the information on the economic and health burden of MS in France and to assess the impact of fatigue and cognitive symptoms on daily living.
Previous analyses of costs of MS conducted in Europe or in other parts of the world have demonstrated that costs are largely driven by the progression of patients to severe stages of disability. The use of DMTs has been recommended in the early stages of the disease, and the value of this strategy lies in the expectation that progression will be slowed. With new treatments entering the market, some DMTs may have an effect on progressive forms of MS, with an increased impact on healthcare costs. It will therefore be crucial to consider when it is clinically meaningful to extend the prescription of DMT to all stages of MS, to define responders and to identify those patients who are better treated with symptomatic agents. Also, it will be important to include patients’ perceptions about their HRQoL. Utility provides important information from the patients’ perspective, and as in previous studies, our results show how rapidly utility decreases with advancing disease. However, cross-sectional data do not allow linking response to DMTs to better utility, and it will be important to investigate this in special outcome studies or registries.
Participation in our study was disappointing. The earlier similar study performed in 2007 with one of the two patient organisations included 1400 participants, 5 while this study enrolled less than 200 patients from the patient organisations. The reasons for this are not clear, but one could speculate that patients have been contacted too frequently in recent years for surveys. Also, the time of data collection in France was very short, due to the excessively long delay in response from the CCTIRS and the CNIL (more than 1 year). We therefore complemented the sample with close to 300 patients from MS clinics. Unfortunately, an additional 50 questionnaires were lost in postal transfer. As a consequence, the results for the severe patient group are somewhat weak, as no group above EDSS 6 reached the target of 50 patients. This illustrates the challenge of performing economic studies in France where public databases are not easily accessible. Recently, an analysis of data from the social health insurance (CNAMTS) identified 49,413 patients with MS through the classification of ALD (‘affection de longue durée’, chronic disease). 7 However, the data set related to 2004 and has thus a limited relevance in 2016.
On the other hand, our sample appears to be very close to prevalence and disease severity in the OFSEP registry. 23 Thus, for the French study, one could argue that the mean annual cost of €31,500 per patient in our study may closely represent the actual average cost per patient in France.
Our results cannot be compared directly to earlier surveys, even if they used similar methodology. With earlier diagnosis, the age and EDSS distribution even within the groupings of mild, moderate and severe can differ, thereby affecting costs. 24 Other differences will stem from differences in methodologies, the timing of the study and changes in healthcare provision. A comparison will thus require careful consideration of all details and will be performed separately for the full study series of 2005 and 2015.12,13 Here, we will limit the comparison to healthcare and community costs for France. In the 2005 study, annual direct costs per patient (adjusted to 2015 prices using the consumer price index) were €20,800, compared to €21,800 in this study. Thus, although in 2015 participants were slightly younger (47 years compared to 49 years) and had a lower mean EDSS (3.6 compared to 4.4), total direct costs have increased. DMT costs represented 50%, which was, however, almost totally offset by substantial decreases in hospitalisation, consultations and investments. Our data do not allow an analysis of the reasons for these changes in detail, but in part they may be due to the lower EDSS score and a lower proportion of patients with a relapse (15% compared to 25%), partly a consequence of the general trend for more outpatient treatment.
In conclusion, our study confirms that most of the costs are due to DMT in early disease with mild disability and to production losses, services and family help at later stages with higher EDSS scores. However, it has to be underlined that symptoms such as fatigue and cognitive limitations are not captured by EDSS and may be the cause for patients having to leave the workforce early despite very low EDSS levels. MS has seen an impressive therapeutic progress, but there remains a more invisible untreated disability that strongly impacts patients’ activities and QoL.
Footnotes
Acknowledgements
The authors are grateful to Bastien Roux and Guillaume Molinier (LFSEP) and to Julie Deléglise and Carole de Mulatier (UNISEP) for making the survey available to members; to Profs David Brassat, Eric Berger, Jean-Philippe Camdessanché, Jonathan Ciron, Pierre Clavelou, Marc Debouverie, Arnaud Kwiatkowski, Jean Pelletier, Jèrôme de Sèze and Patrick Vermersch (SFSEP) for enrolling participants to the survey; to Jennifer Eriksson and Johan Dalén (MAPI Group) for organisational and statistical support; to Markas Gedminas (Medscinet) for construction of the on-line 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: C.L.-F. has received consulting fees from Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva. G.K. has received consulting fees from Almirall, Bayer, Biogen, Merck Serono, Novartis, Oxford PharmaGenesis, Sanofi Genzyme and Teva. J.B., D.C. and M.G. were at the time of the study employed by the MAPI Group, a 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.