**Abstract**

Rare diseases affect less than 1 in 2000 or 5 in 10,000 people by definition. Most of those diseases have genetic basis (80% of cases) and first symptoms appear in early childhood (50% of cases). Most of these diseases are chronic and degenerative and pharmacotherapy is not available for many of them. Until today, there are more than 7000 rare diseases. In Serbia, the problem of diagnosis and pharmacotherapy of rare diseases is currently under public scrutiny. Patients who suffer from rare diseases in Serbia face many challenges in terms of awareness, timely diagnosis, and adequate treatment. These people are often misdiagnosed or the diagnosis is delayed due to several problems: lack of awareness among medical professionals, lack of expertise, unavailability and/or high costs of diagnostic tests, etc. According to the National Organization of Patients with Rare Diseases in Serbia (NORBS), many diagnostic procedures have to be conducted abroad and the process comprises many difficulties: high costs, travel expenses, or transportation of biological material. Although national legislation ensures the availability of drugs for those diseases, pharmacotherapy is faced with many problems. In this work, we aim to show that improvement of the knowledge regarding rare diseases among both professionals and patients represents a crucial step for enhancement of perspectives for those patients in our community.

**Keywords:** rare diseases, pharmacotherapy, physicians, patients, knowledge, attitudes

### **1. Introduction**

A rare disease or an orphan disease represents any disease that affects a small percentage of the population. According to data from Europe, a disease or disorder is defined as rare when it affects less than 1 in 2000 citizens (there are so rare diseases that affect 1 person in 100,000 or even less) [1].

The most significant matters concerning rare diseases (RDs) are as follows: (1) these diseases are often chronic, progressive, degenerative, and life-threatening; (2) most of them (80%) have identified genetic base; (3) in the majority of cases (75%), the first symptoms appear in early childhood (30% of rare disease patients die before the age of 5); (4) RDs represent disabling conditions: they have tremendous social and socio-economic impact on one country, because they affect not only the patients but also their families and the whole society.

It is estimated that more than 7000 rare diseases have been detected and described so far. European Organization for Rare Diseases (EURORDIS) represents a unique, non-profit alliance of rare disease patient organizations from 72 European countries. According to this organization, 30 million people in Europe suffer from some of the numerous rare diseases. A similar organization exists in Serbia (NORBS), which estimates that such patients are about half a million in our community [2].

Patients suffering from RDs are faced with numerous complications: deficit of public and scientific education of the diseases, delay in diagnosis (or lack of access to correct diagnosis), heavy social consequences (stigmatization, isolation, discrimination, reducing professional opportunities, etc.), lack of appropriate quality healthcare, high prices of these drugs and complicated procedures for their procurement, etc. [3]. Also, people affected with RDs may require other medicinal devices (diapers, special nutritional preparations, wheelchairs, etc.). The fact that these expenses are not reimbursed by the national health insurance represents additional problem in everyday life of these patients and their family. All these obstacles have led to many charitable actions aimed at collecting donations in order to improve treatment solutions as well as to involve media in raising public awareness of this topic [2, 3].

Although national legislation ensures the availability of drugs for those diseases, ("orphan drugs"), the National Register of RDs still does not exist in Serbia. It is important to know that there are hospital registries for some rare diseases but a systemic and universal approach is still missing. Additionally, most of these conditions are not coded in the ICD-10, which only has codes for 500 of the rare diseases [4].

Beside this, pharmacotherapy of rare diseases in our country is also challenged with many difficulties, not just due to legislative obstacles. Although there are not enough registered orphan drugs, many of them can be found on the "black" market, in private pharmacies at very high prices and without adequate supervision [5].

Serbia has made certain progress in the area, but numerous unresolved issues remain. It should be point out that the importance of this topic was recognized in our country for the first time few years ago, in 2014. At that moment, certain amendments displayed the need for the development of centers for rare diseases and also declared this group of patients as a special category with the right to use free health insurance. In addition, a special budget from the Ministry of Health was assigned to finance treatment with orphan drugs [6, 7].

In addition to the above, National Organization for Rare Diseases in Serbia (NORBS) represents a non-governmental, non-profit organization that was founded in 2010 with an aim to improve the quality of life for people affected with RDs in Serbia.

## **2. Rare diseases patients as vulnerable subjects in clinical trials: bioethical challenges**

The particular question that arises here is related to bioethical aspects of pharmacotherapy of these diseases and all obstacles along the way of examination of special kind of drugs intended to treat small number of patients (the so-called orphan drugs).

The issue of ethical and bioethical aspects of experiments including humans (which was the forerunner of clinical trials) was almost completely ignored by medical ethics of the late nineteenth and early twentieth century. It is relevant to mention that the sensitivity toward medical research subjects belonging to

#### *Pharmacotherapy of Rare Diseases in Serbia: The Current State of Art DOI: http://dx.doi.org/10.5772/intechopen.91262*

vulnerable groups was first expressed clearly in the Declaration of Helsinki (it was adopted by the 18th World Medical Association General Assembly in Helsinki in 1964, and revised several times (most recently in 2013) [8].

Generally, patients suffering from rare diseases could be considered as the members of vulnerable groups. As we already mentioned, most of these conditions are chronic, degenerative, and life-threatening, of unknown or genetic origin, and mainly affect children [2, 3]. Some of these diseases have a devastating impact on all aspects of the patients' lives and their careers. Additionally, the development and availability of drugs for RDs could challenge basic bioethical principles. Four commonly accepted principles of health care ethics, excerpted from *Beauchamp and Childress***,** include the: (1) principle of respect for autonomy, (2) principle of non-maleficence, (3) principle of beneficence, and (4) principle of justice [9].

The first bioethical principle—respect for the autonomy of the patient—means that the patient has the capacity to act intentionally, with understanding, and without controlling influences that would mitigate against a free and voluntary act. This principle is the basis for the practice of "informed consent" in the physician/patient transaction regarding health care, which represents one of postulates of modern clinical trial. The principle of non-maleficence requires us, as medical professionals, to not intentionally create harm or injury to the patient, either through acts of commission or omission. The meaning of the Principle of Beneficence is that health care providers have a duty to be of benefit to the patient, as well as to take positive steps to prevent and to remove harm from the patient. Finally, justice in health care is usually defined as a form of fairness, or as Aristotle once said, "giving to each that which is his due." [9].

In addition to the above, the utilitarian concept of bioethics could not be fully applied in this matter since it favors development of drugs for common disorders instead of the rare ones. One could argue that diseases are rare but there are a lot of patients suffering from them [5, 6]. These diseases represent a challenge not only for the individual and the family of the patient but also for the medical professionals, the entire health care system, and the complete society.

By considering the patients suffering from rare diseases as the members of vulnerable groups, we want to stress the presence of individualized medicine trend in contemporary medicine. Ethical declarations, codices, bioethical documents, and the function of the ethical committees were the indicators of individualizing medicine trend. Regarding the rare diseases issue, the indicators of individualizing medicine trend are certain documents: (1) EU Regulation on Orphan Medicinal Products (1999); (2) EU Regulation on Pediatric Drugs (2006); (3) Programme of Community Action in the Field of Public Health (2007–2013); and (4) EU 7th Framework Programme for Research (2007–2013) [8].

It can be concluded that above-mentioned case of "moving" from a random sample of hospitalized patients to specific group of patients, members of vulnerable groups, is the indicator of individualizing medicine trend and it continues to develop. One of its goals is certainly, we consider, the rare disease issue and the specific patient-physician encounter that includes the rare disease patient, namely, the patient *sui generis* as the subject of specific therapeutic research [8].

### **3. The aim of our study**

Our research group deals with different aspects of rare diseases in our community: pharmacotherapy, bioethical issues, social significance, importance of education among medical students, patients, and professionals, etc.

In the first part of this work, we will briefly present the main results of the pilot study regarding pharmacotherapy of rare diseases conducted among physicians and clinical pharmacists who deal with these kinds of patients in Serbia.

In the next part of examination, we will present the main results of the survey conducted among patients suffering from rare diseases in our country.
