Out-of-Pocket Healthcare Expenditures of Households Living With Rare Diseases

Background: Economic impact of rare diseases for both individuals and family members, in addition to many expenditures such as disease-related medication, use of healthcare, access to treatment, special medical and nutritional requirements; it also causes indirect effects such as loss of productivity, loss of wages, health insurance and inability to �nd work. In this study, it is aimed to determine the out-of-pocket health expenditures and economic burden of households where individuals with rare diseases live in Turkey. Methods: The research population consists of registered members of associations that are members of the Rare Diseases Network. The questionnaire was developed based on literature review and expert opinion and the online survey was made available between 01.05.2020- 31.05.2020. After obtaining data on out-of-pocket expenditures in rare diseases, the necessary analysis was carried out through the Microsoft O�ce Excel application. In addition to the general analysis involving all participants, expenditures on the basis of disease group and disease were calculated. The costs calculated in Turkish Liras (₺/TL) have been converted to Euros (€) according to the average exchange rate for 2020. Results: 456 participants were included in the analysis. Accordingly, 233 patients were included in the metabolic diseases category, 178 in the neuromuscular system diseases category and 41 in the others category. It was determined that special nutrition were the highest expenditure group and emergency department were the lowest expenditure group. The lowest amount of out-of-pocket expenditure is in the metabolic diseases group. It has been observed that 47.35% of all participants allocate more than 10% of the annual average household income and 4.65% more than 100% of the annual average household income for medical expenses. It is seen that the average out-of-pocket expenses in DMD, SMA, cystinosis and cystic �brosis diseases are close to each other. Conclusion: Since individuals with rare diseases are often unable to work, out-of-pocket expenditures related to the disease lead to �nancial di�culties and even impoverishment. Their already di�cult lives get even more di�cult by the �nancial sacri�ces made for treatment. Treatments for rare diseases need to go beyond special exclusivity for patient access and reimbursement.


Introduction
Rare diseases are life-threatening, serious, genetic, chronic, complex, demanding and low prevalence diseases [1][2][3]. Rare diseases other than genetic ones are generally cancer, autoimmune diseases, degenerative and proliferative diseases or diseases caused by infection and infestation [4]. Although de nitions of rare diseases vary; diseases affecting less than 200.000 people in America, 50,000 in Japan, and 2,000 in Australia are considered as rare diseases [1,3,5]. Yet according to the report published by the World Health Organization (WHO) in 2013, if the number of people affected is less than 5 out of 10,000, the disease is considered a rare disease [2].
It is estimated that there are more than 7,000 different types of rare diseases. This number makes up 6-10% of all diseases in the world [6]. However, epidemiological data in the world are constantly changing and a new rare disease is being discovered every week. A disease that was considered rare in the past can become an epidemic/widespread disease today. Similarly, the diseases that are considered rare in one region may not be so in another region [1].
Rare diseases that negatively affect the patient's quality of life and dramatically reduce life expectancy manifest themselves by serious mental and physical disorders [7]. Since they are not well known, occur in unusual ways and often in comorbidities; rare diseases are also di cult to diagnose. On the other hand, diagnostic methods and possibilities are not available for many rare diseases. In addition, the number of doctors who can diagnose and treat rare diseases are quite limited [8]. Only 1% of known rare diseases have been approved for orphan drug treatment [9]. For these reasons, rare diseases with di culties in diagnosis, treatment and follow-up require to be handled differently from other diseases [7].
Turkey's de nition of rare diseases is 50 times less common than the European Union and the United States, and diseases with a prevalence of roughly 0.1-9% for every 100,000 people are considered rare. In this context, it can be said that fewer diseases are considered rare in Turkey than in the European Union [10][11].
Turkey is a country where rare diseases are frequently seen because of inbreeding and different ethnic structures. Due to inbreeding, the prevalence of rare diseases in Turkey is higher. While the rate of inbreeding in European Union countries is 3-10‰, the proportion of inbreeding in Turkey is 12-17%. Therefore, it is likely that approximately 5-7 million people in Turkey suffer from rare diseases [12].
Economic impact of rare diseases for both individuals and family members, in addition to many expenditures such as disease-related medication, use of healthcare, access to treatment, special medical and nutritional requirements; it also causes indirect effects such as loss of productivity, loss of wages, health insurance and inability to nd/leave work [13]. The loss of income caused by the inability of individuals with rare diseases to participate in the working life and the fact that one of the households quits their job to care for the individual with the rare disease brings with it the individual and social economic burden [14].
As in many countries of the world, there are problems in Turkey due to lack of knowledge about rare diseases, lack of specialist physicians in these elds, high costs of treatment of the diseases and lack of legal regulation regarding rare diseases and orphan drugs [12]. In particular, the low number of individuals with rare diseases causes not to be given priority in the health system and the public, and this results in problems in accessing health services [14]. Rare diseases differ from other diseases with their characteristics such as disease-speci c drugs, treatments, medical tests, special nutrition programs, medical devices and consumable requirements [2]. However, every patient has equal rights when it comes to the right to health. Due to the rarity of diseases and limited demand for the treatment of these diseases, government support is very limited [3].
Recently, there has been a growing awareness all over the world, including Turkey, about the quality of life of individuals with rare diseases, the availability of orphan drugs and the cost of medicines. However, most countries have not studied the use of healthcare, drug use and the economic burden on the speci c needs of individuals with rare diseases [15]. Health expenditures of people with rare diseases that are not covered by the government and have to be paid out-of-pocket place a great burden to the individuals and families [16]. Out-of-pocket health expenditures include payments made by individuals for the healthcare they receive and are not reimbursed by any person or institution [17].
In this study, it is aimed to determine the out-of-pocket health expenditures and economic burden of households where individuals with rare diseases live in Turkey.

Method
In order to carry out the research, the necessary permission documents have been obtained from the Social and Human Sciences Research Ethics Committee of Ondokuz Mayıs University.

Research Population
The research population consists of registered members of associations that are members of the Rare Diseases Network. Although there are approximately 4,000 individuals with rare diseases registered in the Rare Disease Network, no sample was selected from the research population and it was aimed to reach the entire population. Only individuals with rare diseases and willing to participate in the research were included in the study. In cases such as the fact that the individual with rare diseases is a child, is illiterate, does not have the necessary information; the necessary data were obtained from their parents.

Research Questionare
Within the scope of the study, a questionnaire was used by individuals with rare diseases and their families as the data collection tool to determine out-of-pocket expenditures related to the disease in the last 1 year. The questionnaire was developed based on literature review and expert opinion.
The rst part consists of 14 questions to determine the demographic characteristics of the individual with rare diseases, the second part consists of 11 questions about the rare disease which the person has, and the last part consists of 30 questions about the nancial expenditures caused by the disease.

Data Collection
The questionnaire was nalized by working with the members of the Board of Directors of the Rare Disease Network. After conducting the pilot study with a certain number of households, the necessary arrangements were made, and the online survey was made available between 01.05.2020-31.05.2020. In order to access the online survey, households have been given the necessary announcements and information by the Board of Directors of the Rare Diseases Network via e-mail.

Data Analysis
After obtaining data on out-of-pocket expenditures in rare diseases, the necessary analysis was carried out through the Microsoft O ce Excel application. In addition to the general analysis involving all participants, expenditures on the basis of disease group and disease were calculated. The costs calculated in Turkish Liras (₺/TL) have been converted to Euros (€) according to the average exchange rate for 2020.

Descriptive Findings
Among those submitted questionnaires, the number of households with rare diseases who participated in the study was 472. Following the examinations, the appropriate and complete llings were detected and the answers of 452 participants were included in the analysis. Estimated respond rate was calculated as 11.8%.
However, since there are 2 individuals with rare diseases in 4 households, the total number of individuals with rare diseases was 456. The rst part of the research questionnaire contains demographic information about the individual with rare diseases. Data on the demographic information of individuals with rare diseases participating in the survey are presented in Table 1. The average age was 11.7 for the group of participants with rare diseases, the youngest of whom was 1 and the oldest was 70 years old. Among the total participants in the questionnaire, the occupational information about the occupational elds and annual income of 30 individuals with rare diseases who are working and retired are presented in Table 2.

Findings About the Diseases
In the second part of the questionnaire, there are questions about the rare disease that individuals who participated in the research have. Rare diseases identi ed were examined under the category of metabolic diseases, neuromuscular system diseases and others according to the type of the disease. Accordingly, 233 patients were included in the metabolic diseases category, 178 in the neuromuscular system diseases category and 41 in the others category. Information on the diagnosis of the rare disease that the participants have is presented in Table 3.

Findings About the Expenditures
After obtaining data on the treatment services, doctor's examinations, medications, medical supplies and access to treatment of individuals with rare diseases; out-of-pocket expenditures were determined in relation to the disease. Analysis of the expenditures of individuals with rare diseases was carried out of 452 households. These expenditures are determined on the basis of expenditure items according to the usage and payment status of the individual with rare diseases. When the expenditures for the entire group of participants were examined, it was determined that special nutrition expenditures were the highest expenditure group and emergency department expenditures were the lowest expenditure group.
Transportation, food and accommodation expenses for access to healthcare services are second in total expenditures after special nutrition (Table 4).
Following the general analyses of all participants, out-of-pocket expenditures were examined on the basis of disease group. For 233 people in the metabolic diseases group, the average out-of-pocket expenditure in the last year was lower than the general average. Special nutrition expenditures constitute the highest expenditure group for metabolic diseases (Table 5).
Neuromuscular system diseases group is the disease group with the highest average out-of-pocket expenditure. Special nutrition, medicine and transportation-food-accommodation expenditures are the items that are spent at similar rates after medical and non-medical devices and supplies. (Table 6).
In the others group, the average out-of-pocket expenditures are close to the neuromuscular system diseases group and are higher than the general average. Other diseases include transportation-foodaccommodation, laboratory and imaging tests, and high expenditure items for medical and non-medical devices and materials (Table 7).    In addition to the analysis carried out on the basis of disease groups, average out-of-pocket expenses were compared according to average annual income. When examined for all participants; it is possible to say that out-of-pocket expenses related to the disease makes up of 30% of the average annual income of the household of the individual with the rare disease. When examined on the basis of disease group, the average amount of out-of-pocket expense according to average annual income shows similar results in neuromuscular system diseases and other diseases groups. The average out-of-pocket expenditures based on their average annual income is the lowest in the group of metabolic diseases (Graph 1). When a household member quits their job to care for the patient, it creates a loss of income. Adding the total loss of income to the total out-of-pocket expenditures makes up the cost of the disease. When evaluated for all participants, the average cost of rare diseases was found to be ₺22,796 (€2,883). The costs of the diseases were found to be ₺20,283 (€2,565) for the metabolic diseases group, ₺25,720 (€3,253) for the neuromuscular system diseases group, and ₺25,629 (€3,242) for the other diseases group.
When all participants' out-of-pocket expenses are evaluated; 72.26% of the total expenses were allocated to medical, and 27.74% to non-medical expenses. When the reimbursed amount is subtracted from medical expenses; it has been observed that 47.35% of all participants allocate more than 10% of the annual average household income and 4.65% more than 100% of the annual average household income for medical expenses. This rate shows similar results for all disease groups. When the amount reimbursed from non-medical expenses is removed; it was observed that 22.79% of all participants allocated more than 10% of their average annual household income and 1.11% allocated more than 100% of the average annual household income to non-medical expenses. This rate was found to be higher in the others group (4.88%) than the rest of the disease groups (Table 8). In addition to general analyses involving all participants and analysis according to the disease group, out-of-pocket expenses were analyzed on the basis of disease. This analysis included the rare diseases that more than 10 people had among all the rare diseases that the participants had. Accordingly, it was observed that the average out-of-pocket expense was in the lowest in albinism disease and the highest in extrophy vesica disease. In addition, it is seen that the average out-ofpocket expenses in DMD, SMA, cystinosis and cystic brosis diseases are close to each other (Table 9).

Discussion
Compared to other diseases, rare diseases show very different characteristics on diagnosis and treatment stages, and disease processes. However, due to the low prevalence in the general population, rare diseases are often an area that is not emphasized, and the policies are inadequate. For this reason, it is of great importance to determine the economic burden that individuals with rare diseases and their families are subjected to, and to organize development policies. In this study carried out with this speci c purpose, out-of-pocket expenditure of individuals with rare diseases and their families were analyzed.
According to the analyses, the average age of the participants was found to be quite low. Considering that the rare diseases mostly affect children; it is an expected result that the average age of the participants is 12. The fact that 95% of the participants are single, 40% are illiterate, the rate of primary school graduates is very low, and the working population is only 7% can be explained by the low average age. In addition, the vast majority of individuals with rare diseases have di culty participating in education and work life due to their diseases. This situation is caused by the physical limitations they experience, those limitations making it di cult to continue their education and business life, the di culties in participating in social life due to the lack of awareness and consciousness in the society, the di culties they experience in nding a job and the treatment processes making it di cult to participate in education and business life.
92% of participants are covered by general health insurance, almost 3% are covered by private health insurance, and 5% have both types of insurance. Although all participants are covered by insurance, enormous out-of-pocket expenses indicate that there are unmet needs in rare diseases.
When the total out-of-pocket expenditures related to rare diseases are examined, from highest to lowest; special nutrition expenditures (25.86%), transportation/accommodation/food (16.91%), medical and nonmedical devices and supplies (14.87%), medicine (12.11%), patient care (7.65%), laboratory and imaging tests (6.94%), hospitalization (5.62%), specialist visits (5.09%), traditional and complementary medicine (4.49%) and emergency department services (0.45%). The fact that special nutrition expenditures account for a quarter of all expenditures shows how big food expenditures are in these diseases and that there is no improvement in this eld since there is no awareness in our country about this issue. According to a 2019 study with rare disease sufferers, it was determined that 28% of the di culties encountered in the treatment process in rare diseases were caused by management/system and policy, 23% from access and 19% from nance. These challenges are; the lack of coverage of treatment services and medicines, the low coverage of medical devices, the expensiveness of low protein products, the lack of reimbursement due to the high costs of genetic therapies to correct the mutation seen in rare diseases, and the failure to cover certain disease-speci c foods [18]. The study found that many of the di culties experienced in rare diseases are due to economic problems related to treatment and medicines, food and medical supplies needed.
According to the results of the analysis, it was observed that the participants had an average income of 30.70% lower than the average household income announced by TURKSTAT. This rate shows similar results for all disease groups. It is thought that this is due to the fact that when there is a rare disease sufferer in the household, one of the households usually quits for care or can only work in part-time jobs for short periods. Although the average household income is low, according to the data released by TURKSTAT, per capita expenditure on health in 2019 is ₺2,434 (€307), while according to this study, almost 6 times more health expenditures are made out-of-pocket in individuals with rare diseases.
When evaluated according to the disease groups, it was observed that the average annual out-of-pocket expenditure in diseases in the neuromuscular system and the other diseases groups were very close to each other and higher than the general average. The average annual out-of-pocket expenditure rate of the metabolic diseases group is lower than the other diseases groups and the general average. Similarly, when evaluated according to the average annual income; while out-of-pocket expenditures made for diseases in the neuromuscular system and other diseases groups cover 35% of the average income, this rate is around 26% in the metabolic diseases group. When examined on the basis of expenditure for each group; it was observed that the area that was paid the most is special nutrition expenditures (39%) in the metabolic diseases group, medical and non-medical devices and materials expenditures (22%) in the neuromuscular system diseases group, and laboratory and medical imaging tests expenditures (18%) in the others group.
Of the studies on the subject, the study by Lopez-Bastida and his colleagues (2016) analyzed the quality of life and annual expenditures of individuals with rare diseases and their caregivers for speci c countries [19]. In the study, the difference of the areas spent according to the type of disease and the costs varying in different countries are noted. This is due to the difference in the use of medicines and healthcare that are approved and covered by reimbursement in each country. Similarly, the study conducted by Gong and his colleagues (2016) examined the availability and affordability of orphan drugs in China. The average cost of 23 orphan drugs analyzed in the study was found to be $4,843.5, which equates to the 505.6-day net income of a middle-income individual. The study results show that the availability of orphan drugs in China is not only very low (20.8%), but also the drug costs are unaffordable for most patients [20].
The economic cost of the disease includes similar results in neuromuscular system diseases and other diseases groups, while it is lower in the metabolic diseases group. It is thought that this is due to the fact that participants with neuromuscular system diseases and other diseases groups with rare diseases are more di cult to care for, therefore the total loss of income is also higher because one of the households quits their job. When evaluated for all participants; It was observed that the economic cost of the disease was above 10% of their average annual income of 70.13% of the participants and above their average income of 26.11%.
Considering the out-of-pocket expenditures of all participants based on their average annual income, it is seen that the participants allocated 30% of their average annual income to expenditures associated with their rare diseases. It was observed that 7.74% of the participants allocated more than all of their average annual income and 59.51% did more than 10% of their average annual income to out-of-pocket expenses associated with rare disease. It is understood that households experiencing this situation maintain their lives through nancial support provided from non-governmental organizations, municipalities, patient associations or by friends, relatives, neighbors and through bank loans and/or borrowing. Excessive outof-pocket expenses can result in catastrophic expenditures. The catastrophic effect occurs when health expenditures exceed a certain threshold and often has an impoverishing effect on households. Although there are two different threshold de nitions in the literature, expenditures above 10% of household total income and 40% of non-food expenditures (payment capacity) are considered catastrophic [21]. When evaluated in accordance with this explanation, it can be said that almost 60% of participants with rare diseases are exposed to catastrophic health expenditure.
Among all diseases, rare diseases of more than 10 people were specially analyzed, and it was seen that the highest average out-of-pocket expenditure among these diseases was in extrophy vesica disease. In addition, the average out-of-pocket expenditure in DMD, cystic brosis, cystinosis and SMA disease are similar. The disease with the lowest out-of-pocket expenditure was determined as albinism. The area of expenditure according to the type of disease also varies. Although out-of-pocket expenditure amounts are similar, when evaluated on expenditure group basis; Medical and non-medical devices and supplies in albinism (32%) and SMA (41%), special nutrition in DMD (20%) and phenylketonuria (71%), and transportation/accommodation/food expenses in patients with extrophy vesica (47%), cystic brosis (24%) and cystinosis (32%) were found to be the highest expenditure groups. In the research conducted by TURKSTAT, out-of-pocket expenditure per capita for 2019 was found to be ₺407 [22]. Statistics on outof-pocket health expenditures, including TURKSTAT data, omit the costs in accessing the healthcare.
According to the general average, approximately 31 times the expenditure is made in households where individuals with rare diseases live. This, in addition to being economically destructive, also brings about health inequalities.

Conclusion
This study is of great importance in order to ensure a clear picture of the economic di culties experienced by individuals with rare diseases. Since individuals with rare diseases are often unable to work, out-of-pocket expenditures related to the disease lead to nancial di culties and even impoverishment. Their already di cult lives get even more di cult by the nancial sacri ces made for treatment. Treatments for rare diseases need to go beyond special exclusivity for patient access and reimbursement.
For this purpose, it is necessary to ensure that patients have complete and unrestricted access to treatments, that access to treatment not only in big cities but also in every patient's own city, that insurance coverages related to treatment and medicine are expanded and regulated according to current market gures, that special needs related to the disease are not dependent on the patient's ability to pay, and that the national plan for the rare diseases missing in our country should be prepared as soon as possible. The cooperation and support of all responsible stakeholders such as patients, patient relatives, associations, physicians, political actors and sector representatives will make signi cant contributions to the solution of the problems experienced by patients. Consent for publication: Informed consent to participate in the study was obtained from participants or their parent or legal guardian in the case of child or baby.

Abbreviations
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests: The authors declare that the research was conducted in the absence of any commercial or nancial relationships that could be construed as a potential con ict of interest.  Figure 1 Average Annual Income and Average Out-of-Pocket Expense