Orphan diseases and associated problems

Introduction

Orphan pathology includes diseases that are very rarely diagnosed in the human population. They can be progressing and life-threatening to patients if they do not receive proper therapy. Often, such diseases end up in a patient’s disability. The European Union criterion for orphan pathology is the occurrence rate that should not exceed 1 case per 2000 people. In the USA, this ratio is 1:1250.

In the Russian Federation, orphan diseases include pathologies with an occurrence rate of 1:10,000 and rarer. There are several definitions of orphan diseases in Russian publications. The most frequently used definition is rare pathology revealed at a low occurrence rate, life-threatening, or constantly progressing that can lead to lethal outcome or disability if not treated.

According to the Federal Law FZ No. 323 dated November 21, 2011 “Healthcare principles in the Russian Federation”, an orphan disease is a pathology that is revealed not rarer than in 10 people out of 100,000.

Orphan diseases in the human population

The spread of orphan diseases in different countries varies significantly. For example, in Polynesians that live in Hawaii, the occurrence rate of mucoviscidosis is 1:90,000 children, and in Russia, this ratio is 1:10,000. Sometimes, such a situation can provide a basis for the removal of a nosological entity from a national register if its rate exceeds the threshold level leading to the quantitative variance of statistical data on certain patients in different countries¹.

Because of a long list of orphan diseases (according to the WHO, >7000 positions), the general number of such patients exceeds 5% of the total Earth population^{2 3}.

The prevalence of some orphan diseases (according to the data provided by the European Union) is presented in Table 1 [1].

Table 1

The list of orphan diseases

In Russia, there are 216 groups of diseases that include from 1 to 8 diseases (by ICD-10 code). Around 1000 nosological entities are included in this list. The list is published on the official site of the Ministry of Healthcare of the Russian Federation (www.rosminzdrav.ru/documents/8048-perechen-redkih-orfannyhzabolevaniy). Federal Law No. 323 dated November 21, 2011 (Article 44) establishes several aspects of these diseases. The Ministry of Healthcare forms a list of rare (orphan) diseases based on the statistical data and publishes it on the official site. Some diseases from the list are collected in the Register of nosological entities that are associated with life-threatening conditions and chronic orphan pathologies with progressing development that can lead to disabilities and shortening of life expectancy of patients. The list of orphan diseases is approved by the Government of the Russian Federation dated April 26, 2012 No. 403 (Table 2) [1].

Table 2

It was revealed that in certain countries there were their definitions for orphan diseases and their lists of pathologies that were included in this group of diseases. The number of nosological entities from the list of orphan diseases varies from 214 (in Russia) to 6000–8000 (in Western countries).

In Russia, in 1985, screening of neonates started in maternity hospitals for the diagnostics of genetically determined enzymopathy (phenylketonuria). This pathology leads to severe irreversible pathology of the nervous system associated with the development of mental retardation if it is not treated. In 1993, the state program “Children of Russia” was implemented that included the examination of neonates for the signs of hypothyroidism. The state program “Health” regulated by the decree of the Ministry of Social Development of the Russian Federation dated March 22, 2006 No. 185 “Mass screening of neonates for hereditary diseases” initiated a complex diagnostic for genetic pathology of neonates. In particular, the project includes testing for such diseases as mucoviscidosis, phenylketonuria, congenital adrenogenital syndrome, etc. Besides, children undergo the testing of hearing. In the case of its reduction, the child is directed for extended diagnostic and treatment for hearing impairments.

The plan of neonatal testing includes several obligatory stages: 1) the collection of biomaterial samples in all neonates and its transportation to the laboratory; 2) fast preliminary testing; 3) additional testing of the biomaterial that provided positive results during preliminary testing; 4) treatment of patients and regulatory monitoring of the quality of treatment; 5) family-oriented medical-genetic consulting.

Total screening of neonates together with prenatal examination and family medical-genetic consulting provides a powerful tool for the prevention of genetic diseases in neonates and their spread in the human population.

Difficulties in the provision of medical care to patients with orphan diseases

Orphan diseases create numerous difficulties for patients at the stage of diagnostics and treatment because of the low occurrence rate. Clinical experience is limited when it comes to rare diseases. Thus, their diagnostics can take much time.

In all countries, there are few medical centers specialized in the treatment of rare pathology, and pharmaceutical companies are not interested in the development of new orphan drugs because of a minor target market.

All the mentioned discriminates the rights of such patients to qualitative medical care and the systems of healthcare worldwide tend to develop an effective approach to the management of orphan patients.

Legislative strategy for orphan diseases

The definitions for orphan diseases in different countries vary significantly. In the USA, this category includes pathologies that are diagnosed in not more than 200,000 people. In the majority of other countries, the definition is based on the relative occurrence rate of a specific disease in the human population [2].

The Orphanet official website contains the classification of rare diseases that is used in the information systems of healthcare and studies. Each nosological entity had its unique and constant identification number – ORPHA. The Orphanet system defines an orphan disease as it is stated in the European Union Regulation on orphan drugs (1999). According to the norms accepted in the EU, orphan disease is diagnosed in not more than 1 out of 2,000 people in the European population.

The classification of orphan diseases in the Orphanet system contains a list of diseases with a decreasing occurrence rate. The main characteristics include groups of disorders and impairments, and their subtypes [3].

 Even though orphan diseases are very rare, the total list of these pathologies is so large (6000–8000) that around 400 mln people are diagnosed with them worldwide. Eighty percent of such diseases are genetic. They vary from light to life-threatening by their severity. A lot of orphan pathologies require an early start of treatment, expensive medical care, and drugs. For example, in adults with spina bifida, the costs of medical care are 3–6 times higher than in healthy people. In the USA, the average cost of pharmaceutical drugs for people with orphan diseases is 137,782 dollars per 1 patient (2014) [2].

A significant issue in the treatment of such patients is the great geographical range of such patients, which complicates their concentration in one specialized medical institution, where they could get qualitative medical care.

Another unfavorable factor for patients with orphan pathology is that it is not profitable for pharmaceutical companies to develop and produce drugs for a small target market. In 1983, the US Congress passed a law on orphan drugs, which promoted the production of these drugs proving financial stimuli to compensate for losses in a small market [4]. Besides, in 2001, “Amendments to the medical care for patients with muscular dystrophy” were approved [2]. This amendment aimed to improve the methods of screening, establish cooperation between different specialized medical institutions, and develop educational programs that provide information for specialists on the peculiarities of different types of muscular dystrophy.

Preventive measures, implemented at the national level, play an important role in the fight against rare diseases. In 1998, FDA issued a document that instructed to add folic acid into food products made of cereal grains. This contributed to a decrease in folic acid deficiency in pregnant women and prevented the development of congenital defects of the neural tube in neonates [5].

Presently, cereal-containing products are supplemented with foliates in 86 countries of the world [2]. European Union demonstrates a complex approach to the management of rare diseases that covers all EU countries. All 28 EU countries have a common definition for orphan diseases and their management is subject to Regulation 141/2000/EC on Orphan Medicinal Products. This Regulation promotes scientific research of orphan pathology and development of new orphan drugs. Besides, a national plan on rare diseases (EUROPLAN) was implemented that simplified the establishment of local national strategies on medical help for patients with orphan pathology. These plans have their budget and are subject to strict dates of realization.

In the European counties, there are tax benefits for pharmaceutical companies that develop orphan drugs. Besides, they have exclusive marketing rights for 10 years when their new drug appears on the market.

Thus, despite a small target market, pharmaceutical companies get compensated for their expenses on the development of new orphan drugs [2]. In 2009, the European Health Committee initiated a plan of action on rare diseases, which led to the development and implementation of national plants on rare diseases by the end of 2013.

In 2011, the state program on rare diseases was actively discussed by the EU Directive 24/2011 on the rights of patients in trans-border healthcare. The directive determined the main rules of application for medical help in other EU countries (except for the country of residence). This promoted cooperation between the systems of healthcare of the EU countries, in particular, due to the implementation of European information systems. The latter was established to support the cooperation between European expert centers and specialists from different countries for the exchange of knowledge and development of alternative variants of treatment, promotion of research, and implementation of innovations to provide the best medical help for patients with orphan diseases [6].

The state regulation on orphan diseases started in 2011 in the Russian Federation. According to the approved law “On fundamental healthcare principles in the Russian Federation” dated 2011, regions have to provide orphan patients with the required pharmaceutical drugs.

Decree No. 403 of the Government of the Russian Federation established a Federal Register of patients with orphan pathology that leads to the shortening of life expectancy and disabilities. The register was created to provide orphan patients with the required drugs and components of dietary therapy. It contains personal information including passport data, personal insurance policy number (SNILS), official diagnosis, etc.

Presently, in the Russian Federation, the state program “Seven nosological entities” is being implemented. It is aimed at centralized procurement of pharmaceutical drugs required for patients with certain diseases including orphan (Gaucher disease, mucoviscidosis, pituitary dwarfism, and hemophilia). The procurement of drugs for children is reimbursed from regional budgets.

There are a number of issues that orphan patients and medical specialists face. The most acute of them include:

• the lack of specialized clinics and hospitals with suitable conditions that would provide qualitative diagnostics and management of patients with rare diseases. Besides, there are few experienced specialists in the sphere of orphan diseases;
• the lack of information support for patients and doctors that do not receive enough scientific and medical data on orphan diseases;
• limited effectiveness of precise diagnostic for orphan diseases at the level of primary care and in-patient facilities;
• poor availability of specialized treatment for orphan patients in the subjects of the Russian Federation;
• a lack of developed standards for the management of some specific diseases;
• a lack of educational resources for primary care physicians who manage patients with orphan diseases;
• a lack of federal and regional systems that would provide patients with pharmaceutical drugs. There are no generally accepted methods of pricing for orphan drugs. Many orphan drugs are not manufactured in Russia;
• further legislative acts are required for the improvement of the provision of orphan patients with pharmaceutical drugs.

There are several recently approved documents, including the Decree of the Government of the Russian Federation dated November 26, 2018 No. 1416 “Regulations on pharmaceutical drugs provision” and “Federal Register maintenance” that contribute to the expansion of the orphan patient database and availability of pharmaceutical drugs that maintain organism functioning at the acceptable level. Besides, the introduced changes include additional education of doctors and other medical specialists on the management of patients with orphan pathology. Educational programs and specialized training courses are developed to increase specialists’ qualification. Doctors can participate in the discussion of different aspects of the existing legislation on the issue. The accepted documents aim to attract investors for the development and implementation of Russian orphan drugs.

Russian citizens with orphan diseases often do not have the opportunity to realize their right to pharmaceutical drugs reimbursement because the required drug is either not present or not registered in the Russian market. As a rule, such drugs are very expensive and the state cannot provide full reimbursement for the drug. The normative limits of state reimbursement for orphan drugs often complicate the treatment of such patients.

Below is the clinical case of a child with an orphan disease (inherited metabolic disorders) who lives in the Krasnodar Territory.

Child G., born in 2014, was examined and treated at the Regional Clinical Hospital for children. From the anamnesis: child of the first pregnancy, the pregnancy developed in the conditions of degree I toxicoses in the 1st trimester. Vaginal delivery at term. The mother applied to the local pediatrician for a long-term respiratory infection. The child underwent a biochemical blood assay that revealed a significant increase in the levels of alanine transaminase (ALT) to 145 U/L and aspartate aminotransferase (AST) to 586 U/L. Viral hepatitis was excluded. The child was hospitalized with the diagnosis “Hepatitis, unspecified (non-infectious)” for further treatment and verification of the diagnosis. The child received hepatoprotective therapy and complained about muscle weakness, difficulty in climbing up the stairs, and rare headaches. Objectively: moderate condition by the primary disease, satisfactory status. Physical development below the median level, harmonious: height – 88 cm (10-25 percentile), bodyweight – 12 kg (25–50 percentile), head circumference – 49 cm (25–50 percentile). The skin is smooth and pale. Muscular tonus tends to be hypotonic. Vesicular respiration, without rales. Heart tones are clear, rhythmic, systolic murmurs on top and in the V-point. The abdomen is soft during palpation, not painful. The lower borderline of the liver is 3.5 cm below the costal arch on the right midclavicular line. The spleen is not palpated. The cerebral and meningeal symptoms are not detected. Laboratory findings: biochemical blood assay: AST – 395 IU/L, ALT – 123 IU/L, lactic dehydrogenase (LD) – 1357 U/L, creatinine phosphokinase (CP) — 825 U/L. Immunoglobulins test: IgE – 409.7 IU/ml. Tandem mass spectrometry was performed for the suspected Pompe’s disease. It revealed a decrease in the activity of alpha-glucosidase (0.63 µmol/L/h at the normal rate of 1.0–25.0 µmol/L/h). A molecular-genetic study by the method of direct automated sequencing was used for a complete analysis of the GAA gene. It revealed changes in the nucleotide sequence c.-32 – 13T> G/c.-45T> G in a heterozygous state described in the international database on mutations (CS941489) and changes in the nucleotide sequence c.584T> A that leads to a replacement of p.Leu195Term in a heterozygous state. The child was diagnosed with “Pompe’s disease (type II glycogenosis). Myopathic syndrome”. The child was prescribed with the genetically engineered drug Myozyme (alglucosidase alfa, Genzyme Ireland Limited, Ireland) for enzyme replacement therapy. The drug is indicated for long-term therapy for all forms of this disease. It is the only pathogenetic therapy for patients with this severe progressing inherited disease (1 time every 2 weeks).

Thus, the prognosis of the disease development varies depending on the time of manifestation and expression of symptoms. For early treatment of the disease, it is necessary to diagnose the disease in time, and for the diagnostics of Pompe’s disease, a genetic assay is not the key method. It is enough to evaluate the activity of the enzyme GAA by the method of tandem mass spectrometry.

Prognosis

The presented clinical case shows that orphan disease is a severe life-threatening condition that can lead to a lethal outcome or disabilities in patients when not treated properly. This fact requires the development of a special strategy of management for patients with rare diseases.

Conclusion

The situation with orphan diseases in Russia requires further development, modernization, and regulation by the national regulation and the system of healthcare. It is necessary to improve the cooperation between different medical institutions and develop a general plan of help and management of patients with rare diseases.

A significant role is played by an increase in the availability of pharmaceutical drugs for the specified group of patients. It is necessary to adopt the experience of the European Union on the tactics of cooperation with pharmaceutical companies and provide them with financial benefits for the development of orphan drugs.

Considering the lack of experience in doctors in the management of orphan patients, more educational training should be organized on rare pathologies that would be included in the course on advanced training for medical specialists.

Presently, there is a need for the integration of plans and research on orphan diseases at the international level. This could change the fragmented approach to this issue management and coordinate general effort of the medical society on the statistical accounting, search for effective treatment, development of screening systems of diagnostics, and information assistance to doctors and patients.