Personalized medicine and treatment of rare diseases

Personalized medicine and treatment of rare diseases as a strategic direction of healthcare development until 2020

The author's team under the guidance of:
Sokolov Alexey Albertovich, Vice-President for Medical Affairs of the National Association of Patients with Rare Diseases "Genetics", Doctor of Medical Sciences, Associate Professor, doctor of the highest category graduate of the Presidential Program for training managerial personnel for the national economy 2005

Contact information: 194017, St. Petersburg, Engels Ave., house 50, sq. 60,
tel./fax: +7 (812) 2932438 , e-mail: dr.sokolov@list.ru ; alsok@rol.ru ; mobile phone: +7 (921) 5734898

Members of the author's team:
Karimova Svetlana Igorevna, President of the National Association of Patients with Rare Diseases "Genetics", mother of a child with a rare genetic disease.
Elena N. Zasimenko, Vice-President for Social Affairs of the National Association of Patients with Rare Diseases "Genetics", mother of a child with a rare genetic disease.
Valentina Larionova, Chairman of the Board of Experts of the National Association of Patients with Rare Diseases "Genetics", Head of the Laboratory of Molecular Diagnostics, Doctor of Medical Sciences, Doctor of the highest category

The concept was discussed at the Board meeting of the Association.

Part I. Diagnosis and treatment of rare diseases is an unsolved problem of modern medicineHistorically, domestic medicine is mostly aimed at more or less common and well-known, socially significant diseases.

Patients with rare diseases are one of the biggest problems of the healthcare system (and not only in Russia). Diagnosis of such diseases is often difficult or inaccessible, treatment is often ineffective due to the lack of appropriate medications (treatment methods), the prognosis is disappointing.

The paradox of rarity is that although "diseases are rare, patients with rare diseases are numerous." They probably affect 6-8% of the global human population. Therefore, "it is perfectly normal to have a rare disease." Rare diseases can affect any family, at any time. It's not just "something terrible that happens to others." This is a very cruel reality that can happen to anyone who has a child, or to himself. The composer Ludwig van Beethoven, the artist de Toulouse-Lautrec, and the President of the United States J. J. suffered from rare diseases.Kennedy, the son of Nicholas II, Tsarevich Alexei.

According to experts, there are 5-7 thousand life-threatening rare diseases in the world. Among them there are very exotic ailments like "Kabuki syndrome" (in Europe – about 300 cases), "Pallister-Killian syndrome" (in Europe – 30 cases), progressive bone heteroplasia, Niemann-Pick disease, Gaucher disease and more frequent, such as cystic fibrosis, hemophilia, various forms of cancer, myeloma, Alzheimer's disease, amyotrophic sclerosis, Huntington's disease, etc. But this is not only exotic. Rare diseases also include systemic lupus erythematosus, antiphospholipid syndrome, juvenile rheumatoid arthritis, myasthenia gravis, Guillain-Barre syndrome, primary biliary cirrhosis of the liver, lipoprotein glomerulopathy and other diseases more familiar to hearing.

There are rare diseases in every field of medicine. Approximately 80% of them are of a genetic nature. The remaining cases are the result of infections (bacterial or viral), allergic reactions, exposure to harmful environmental factors, or are degenerative or proliferative in nature.

The number of rare diseases is constantly increasing (5 new pathological conditions are described every week in the world). This is due to both the improvement of diagnostics and the deterioration of the ecological situation on the planet associated with human activity.

According to EURORDIS (European Alliance of Organizations of Patients with Rare Diseases), two–thirds of rare diseases manifest in early childhood, in 65% of cases have a severe disabling course, in 50% - a worsened prognosis for life, in 35% of cases are the cause of death during the 1st year of life, in 10% – at the age of 1-5 years, in 12% – at the age of 5-15 years. Every second patient is accompanied by motor, sensory or intellectual insufficiency, and every fifth patient has chronic pain syndrome.

At the same time, with a timely diagnosis and timely treatment, it is very often possible to completely exclude the occurrence of clinical symptoms of the disease (example: patients with hepatocerebral dystrophy, hemochromatosis, Gaucher disease), and the person remains a full-fledged member of society.

Most rare diseases are characterized by a wide range of disorders and symptoms that vary not only in different diseases, but in different patients suffering from the same disease. Relatively common symptoms may mask the underlying rare disease. In this case, the patient is usually diagnosed with a frequently occurring polyethological, polypathogenetic disease (coronary heart disease, hypertension, cirrhosis of the liver, chronic glomerulonephritis, nephrotic syndrome, multiple sclerosis, chronic recurrent uveitis, schizophrenia, etc.). Making an incorrect diagnosis (for example, coronary heart disease instead of Fabry's disease, multiple sclerosis instead of leukodystrophy, etc.) leads to the appointment of incorrect, often harmful treatment (example: the assumption of an autoimmune disease in a patient with a metabolic disease and its treatment with hormonal and cytostatic drugs).

The search for a rare disease is advisable in all patients with "frequent" diseases, when the existing symptoms do not fully fit into the clinical picture, when clinical manifestations occur at an atypically young age, when it is not possible to choose a treatment, and the disease progresses despite the treatment.

The problems of most patients with rare diseases are similar. These are inaccessibility of correct diagnosis, delay in diagnosis, lack of high-quality information, and often scientific knowledge about the disease, severe consequences for patients from a social point of view, lack of appropriate quality medical care, errors and difficulties in obtaining treatment and care.

A patient with a rare disease is an orphan of the healthcare system, often without a diagnosis, without treatment, without scientific research: and therefore – without hope.

The concept of the rarity of the disease should not mask the importance of the problem that rare diseases pose to public health.

Part II. Treatment of rare diseases – a new paradigm of modern medicineIndividualized medicine and treatment of rare diseases are currently a new concept (model) of healthcare (Model List for Orphan Medicines), which is becoming increasingly widespread in the world.

Originated in the early 80s of the twentieth century in the USA, this direction is now being actively implemented in both developed and developing countries and coexists with the generally accepted concept of treating socially significant diseases using vital medicines (Model List of Essential Medicines).

At the heart of this paradigm is an individual patient with a specific disease. Its key concepts are "rare diseases" and "orphan drug".

What is a rare disease? This is a life-threatening or chronic progressive disease occurring with a certain frequency, without treatment leading to death or disability of the patient. The threshold for classifying the disease as rare differs in different countries and ranges from 1:1500 to 1:2500 of the country's population (in the USA, a rare disease is considered if less than 200 thousand Americans suffer from it, in Japan – if less than 50 thousand Japanese suffer from it, in Australia – if less than 2 thousand Australians suffer from it, in European In the Union – if its occurrence is less than 5:10000, in Canada – less than 1:2000 of the population).

Orphan drug is a medical product designed for the diagnosis, prevention and treatment of a rare disease that has no commercial prospects, but meets the needs of public health. Companies working in the field of medicine, under normal market conditions, are not interested in developing such products that do not have commercial success in the future for economic reasons (primarily due to the high cost of developing and promoting the product to the market and/or due to low demand for it due to the rarity of the disease).

Governments of different countries finance special programs so that the release of "unprofitable" or "orphan" medicines is attractive, and the companies producing them do not work at a loss. In many countries, special legislative acts have been adopted that provide certain benefits to development companies, stimulating the interest of science and business in innovative developments in this area. Incentives may include: exclusive marketing rights for a period of five to ten years; full or partial payment for procedures for obtaining official permission for the use of medicines; the possibility of obtaining financial support from state funds for research in the field of rare diseases; informational and organizational support in the preparation of clinical trial protocols, etc.

The pioneers in this field were the USA. In 1982, a special bureau (Office of Orphan Product Development) was created under the US Agency for Medicines and Food Products (FDA), engaged in the development of "rare products". In 1983, a law was passed (Orphan Drug Act) regulating the status of a rare disease, an orphan drug and approving privileges for development companies and manufacturers, and this concerned not only pharmaceutical and biological drugs, but also medical equipment and dietary food. According to this law, about 1,600 known diseases and syndromes were recognized as rare, and 300 medicines were classified as orphan medicines. Subsequently, similar legislative acts were adopted in other countries – in Singapore (1991), Japan (1993), Australia (1997), South Korea, Canada, Taiwan and, finally, in the European Union (1999). Currently, in many countries, medicines belonging to the rare category make up a whole segment of the drug market with its own rules of production, registration, state support, patent protection, etc.

The fundamental documents in the European Union were the Decision of the European Parliament No. 1295/1999/EC of 29.04.1999 and the Directive of the European Parliament No. 141/2000 of 16.12.1999. They defined orphan diseases and orphan medicines, and identified prospects for their study and treatment. In April 2000, in London, in compliance with the European Directive, the Committee for Orphan Medical Products (COMP - Committee for Orphan Medical Products) was established, which includes representatives of the relevant patient groups. This committee must review the dossier for the medicinal product within 90 days, and within a 30-day period the European Commission must decide on its use throughout the EU. EU Commission Resolution No. 847/2000 of 27.04.2000 established a register of medicines for the treatment of rare diseases. Until February 2007, the orphan drug status was assigned to 450 drugs, and this decision applies to 34 EU countries. According to the President of EURORDIS Terkel Andersen, currently the number of patients with rare diseases in the European Union countries is about 30 million people, i.e. almost every 15th European suffers from a rare disease. Some of them waited for 25-30 years before they were diagnosed correctly.

The scale of the work carried out in the European Union is indicated by the data of the European Database on Rare Diseases, accumulating information from 35 countries. As of March 15, 7242 rare diseases and conditions were registered in it, 1233 clinical laboratories in which 1504 rare diseases are diagnosed, 2003 research laboratories in which 4198 projects on 2040 rare diseases are carried out, 283 registers, 3092 expert clinics, 1739 patient organizations, 10302 medical specialists, 521 medicines that have indications for rare diseases.

Part III. The situation in RussiaThe situation with the organization of medical and social assistance to patients with rare diseases in Russia remains very difficult.

In our country, the problems of only socially significant diseases have begun to be solved, and an individual with a rare disease remains one-on-one with his disease. The existing system of medical care is designed mainly for more or less socially significant groups of patients and practically does not cover rare diseases. Moreover, the problem does not seem to exist, since there is practically no diagnosis and registration of such patients. Meanwhile, taking into account the data of the All–Russian Population Census of 2002, data on the average occurrence of rare diseases in the population, they affect at least 1% of the country's population - 1.5 million people. With improved diagnostics, their number can reach 8-10%. (For comparison: in Russia, according to the Center for Demography and Human Ecology of the Institute of National Economic Forecasting of the Russian Academy of Sciences, there are currently about 2.1 million patients with diabetes mellitus.) What is not a social problem?

The first step to organizing medical care for a patient with a rare disease is to make a diagnosis. Healthcare professionals often have insufficient knowledge of most rare diseases (this problem exists not only in Russia). The lack of information is the basis of diagnostic errors, and this is the source of suffering for the patient and his family, the reason for the delay in providing medical care, sometimes leading to irreversible consequences.

Diagnostic opportunities exist in a number of laboratories of research institutes and universities in Moscow (about two hundred diseases) and St. Petersburg (several dozen diseases) and are practically absent in the regions. Mass screening of newborns, organized during the implementation of the national project "Health", covered only 5 diseases (phenylketonuria, congenital hypothyroidism, galactosemia, adrenogenital syndrome, cystic fibrosis) and is a drop in the bucket compared to the total number of hereditary diseases.

After the diagnosis, the patient needs to be provided with treatment. To do this, in principle, the necessary medicine (treatment method, medical technology) must exist and be registered in our country, and there must be a medical institution in which treatment will be carried out (inpatient or outpatient).

A patient with a rare disease can purchase the medicine he needs himself or get it for free if he belongs to the privileged categories of citizens entitled to receive a set of social services (citizens entitled to DLO (additional drug provision) in accordance with Federal Law No. 122-FZ of 22.08.2004 – "federal beneficiaries"; citizens who have the right to preferential drug provision in accordance with legislative acts adopted in the region of residence – "regional beneficiaries") and/or has a disease included in the state program of drug provision for patients with 7 rare and expensive diseases, implemented since 2008.

Unfortunately, in practice, not everything happens so smoothly, especially with regard to rare and expensive drugs. The standard of expenditure of budgetary funds per patient per month in accordance with the DLO program from April 1 is only 423 rubles, despite the fact that in some cases amounts up to one and a half million rubles are required. As a result, there is an extreme shortage of funding for the program, a persistent defect in expired prescriptions in pharmacies, a shortage of vital medicines and social dissatisfaction, expressed in an increase in the number of refuseniks from benefits (in some regions, the number of "refuseniks" exceeded 60%).

To receive medicine under the federal DLO program, a person must have a disability. What does it mean? Firstly, the fact that the patient cannot receive treatment in the early stages of the disease, when it is most effective, but only when he becomes disabled. Secondly, in cases where the situation is reversible, and as a result of treatment it is possible to achieve a significant improvement in the condition, the patient cannot refuse disability, because in this case he will not have the right to receive medicines free of charge. As a result, instead of preventing disability, its cultivation takes place (it should be emphasized that this applies only to certain diseases).

The "7 nosologies" program was designed to correct the situation, to withdraw funding "expensively" in a separate line. Only its own budget for 2008 amounted to about 33 billion rubles (an amount comparable to the budget of the entire DLO last year). And the result was not long in coming: the provision of rare and expensive medicines has become more planned and regular, there are practically no delays in obtaining drugs in pharmacies, the need for them is practically ensured. To some extent, the "expensive-cheap medicine" conflict has been resolved, and the associated problem of choice: to save one patient or to provide treatment for many. Debts to manufacturers of medicines have decreased, and many of them have returned to the market.

But at the same time, new problems have appeared. The procedure for forming and maintaining a patient register and drawing up a clear system of applications in accordance with real needs has not been defined, as a result of which about a third of medicines are currently "gathering dust" on pharmacy shelves unclaimed, despite the fact that some patients receive medicines in "reduced" dosages, or do not receive them at all. The system of inclusion of newly identified patients in the program has not been worked out. As a result, some of them are forced to wait for the drug they need (often the only one) for up to six months, since tenders for the purchase of medicines and the collection of applications from the regions are carried out once every six months, and the chance to get into the program in the so-called "off-season" is almost zero. Since many of these diseases are severe and progressive, it is not difficult to guess that in six months higher doses of medications will be needed (due to new complications of the disease), or the patient will not wait for his medication at all ... . There is no clear system for monitoring the results of treatment, standards and protocols for the management of patients have not been worked out, or simply they are not applied in practice. The very system of receiving the drug to patients, its use and monitoring of treatment results needs to be revised. The patient receives a prescription medicine in a pharmacy "on hand", carries it "in a string bag" home and stores it in the refrigerator, after which the question arises about ensuring and observing the storage conditions of "thermally sensitive" drugs. Most of the drugs require administration in a hospital, but the procedure of hospitalization there several times a month (and often for life) is extremely complicated and burdensome for both the patient and the doctors. Moreover, in many cases (especially this is typical for remote regions), doctors generally refuse to administer a rare expensive medicine, which is caused by lack of experience, ignorance of pathology and fear of possible adverse reactions (complications). As a result, patients are sometimes forced to travel hundreds of kilometers to central clinics (which for many of them is physically problematic and causes financial problems), or to ask familiar doctors "for an additional fee" to carry out infusions at home. As a result, again, a violation of the frequency and technology of the drug, high risks of complications and a decrease in the effectiveness of treatment.

Of course, a separate program for rare and expensive nosologies is a huge step forward. But we should not forget that these diseases are not seven, but thousands, and many of them are already curable. But the budget for the next three years has already been drawn up, and it does not yet provide a place for new "orphans". Moreover, in the currently discussed concept of the development of domestic medicine for the period up to 2020, the topic of rare diseases and orphan drugs is generally "modestly" silent. And now the words of the mother of twin girls with the rare disease mucopolysaccharidosis type I (which has been treated all over the world for five years, but not in Russia) sound more relevant than ever - "I'm so tired of living next to death! ..".

Depending on the disease, the main method of treatment may be special nutrition (pheniketonuria, galactosemia), taking tablet medications (congenital hypothyroidism), periodic injections of expensive drugs (Gaucher disease, hemophilia, primary immunodeficiency), periodic expensive procedures (LDL apheresis in homozygous familial hypercholesterolemia), etc. At the same time, the patient should be under dynamic supervision, and if necessary, hospitalized in a specialized medical institution (usually federal) that has the capacity to implement and monitor the therapy in accordance with the approved protocol (if any). Currently, such an institution can accept a patient for inpatient treatment if there is a quota (state order) for the provision of VTMP (high-tech medical care). To do this, both the disease itself and the medical institution should be included in the order of the Ministry of Health and Social Development on the provision of high-tech medical care, issued approximately 1 time a year (the last order No. 812 was issued on December 28, 2007). The process of obtaining quotas (like everything in our country related to the distribution of funds) involves certain difficulties and bureaucratic delays, therefore, in the absence of a predictable flow of patients, a medical institution is often not interested in receiving them. An alternative to this option for the patient is to receive paid medical services (example: intravenous infusions of immunoglobulin preparations in adult patients with primary immunodeficiency, because quotas exist only for children).

The lack of continuity between the child and adult health care system is a serious problem in our country. There are examples when a child with a rare disease was adequately treated until the age of 16-18, grew and developed normally. Then his treatment was stopped (what is required for a child in our country is often no longer required for an adult). As a result, decompensation of the disease occurred, and the person died several years later. At the same time, all the efforts and funds invested by the state in his treatment in childhood were in vain.

A complex, complicated system of healthcare financing (financing from different sources), different "schemes" for obtaining medicines, different requirements for prescriptions, different pharmacies, the need to buy constantly absent "preferential" medicines at their own expense, of course, negatively affect the effectiveness of treatment of patients with rare (and not only) diseases and the rationality of spending the funds allocated for this purpose leads to an increase in social dissatisfaction and tension.

The simplest thing is to divide responsibility by command and administrative methods: some medicines or treatment methods (as a rule, the most expensive) should be financed from the federal budget, others from the regional budget, some according to one program, others according to another. In fact, this leads to a cumbersome, unwieldy, invulnerable system of drug provision, at least for certain categories of patients, makes it impossible for a comprehensive system of their treatment to exist. Failure at any stage (delay in the receipt of one of the necessary medicines from the "center", lack of funds for the purchase of another in the "region", inability to monitor and correct therapy in a medical institution, etc.) leads to the loss of precious time, a decrease in the effectiveness and effectiveness of treatment, which brings the patient closer to disability, shortens his life, reduces the return on financial resources invested in treatment.

In some cases, this situation prevents the introduction of new modern medical technologies into healthcare. As an example, the situation with the treatment of myasthenia gravis and Guillain-Barre syndrome can be cited. In the treatment of the most severe forms of these diseases in our country, plasma exchange is traditionally used – replacing the patient's plasma with donor plasma in order to reduce the level of pathological antibodies in the blood. For more than 10 years, modern selective blood processing technologies have been used all over the world instead of plasma exchange. Such opportunities appeared (cascade plasmapheresis) and in our country, moreover, it was possible to significantly (almost 2 times) reduce their cost, and it became even somewhat less than the cost of plasma exchange. However, the introduction of cascade plasmapheresis turns out to be unprofitable for medical institutions, because with a decrease in the cost of donor plasma (funded from other sources), the cost of consumables increases (funded from medical facilities). Other advantages (saving scarce transfusion media, reducing the risk of transmission of blood transfusion infections) are not taken into account.

If the medicine is not registered, the patient has a chance to receive treatment only if he enters the clinical trial program of a new drug, because the legislation of the Russian Federation, namely the law "On Medicines", says that unregistered medicines can be imported into the country only for clinical trials. The main disadvantages of this option are the unpredictability of the result of treatment (for example, in placebo-controlled studies, it is not clear whether the active drug is taken by a patient or a "dummy") and its limited duration. All trials end sometime. And then what?

The current situation contradicts the convention of the World Health Organization (WHO), according to which everyone has the right to adequate treatment and WHO allows the use of drugs registered in other countries, if the patient and his doctor take appropriate responsibility.

The order of the Ministry of Health clarifies that, according to vital indications, the drug can be imported in accordance with the procedure stipulated by the Ministry. But practice shows that if the drug is not registered, it is almost impossible to start treatment.

In this case, the patient himself (or his relative) can buy the drug abroad and inject it for personal use. To do this, firstly, it needs to be sold to him there, and secondly (which is almost impossible) that there is a medical institution that would agree to use it.

Another possible option is to receive the drug for free in the form of humanitarian aid from international charitable organizations. But even here there are pitfalls, and sometimes even insurmountable obstacles, especially if the imported medicine is not registered in Russia. It is practically impossible to do this promptly, without paying the appropriate taxes and customs duties, even if the medicine is necessary for vital reasons, and the patient has no choice and no time to wait. We have organized the delivery of medicines for humanitarian aid to patients with rare diseases (Fabry's disease, mucopolysaccharidosis) three times. The process lasted from 3 to 6 months, it was necessary to collect entire volumes of various approvals and permits. And if it were not for the responsiveness of the people who took part in this, starting from the Ministry of Health and Social Development and ending with customs, these actions would not have been carried out. And the main reason for this is the lack of clearly prescribed rules for the import and use of unregistered vital medicines. The "Regulation on the procedure for the use of medicines in patients with vital indications" regulating these procedures, which received the right to life after the adoption by the Ministry of Health and Social Development of Order No. 494 of August 9, 2005, is applied in practice only in exceptional cases and raises more questions than answers due to the lack of clarity and elaboration of the "order of application" itself. But there are prohibitive laws (categorical Article 22 of the Law "On Medicines", adopted in an obvious hurry with an understandable desire to block the "black" channels of receipt of unregistered medicines under the guise of humanitarian aid and at one moment "tonsured" everyone and everything under one comb, depriving many patients of the only hope and opportunity to receive vital necessities (sometimes – the only possible) medicine. Well, it is always easier to cut the Gordian knot with a peremptory ban than to mess with each specific case and solve the problem of an individual. But why is it in our country, unlike the rest of the civilized world, that heroic efforts need to be made to solve a not so difficult issue?

What prevents the registration of rare (and not only) medicines in our country? The fact that the registration process, due to an unnecessarily complicated, extremely complicated bureaucratic procedure, takes too long in practice and requires a lot of effort, time and finances from the manufacturer of a rare medicine. That is why most companies are in no hurry to register their products in Russia, especially among those engaged in the production of "orphan medicines".

It should be recognized that at present the situation has begun to change for the better. The Federal Service for Supervision of Healthcare and Social Development, in accordance with paragraph 10 of Article 19 of the Federal Law "On Medicines", has developed a Regulation on the accelerated procedure for state registration of Medicines (Roszdravnadzor Information Letter No. 01I-53/08 dated 02/18/2008). It concerns medicines intended for the treatment of rare diseases, some epidemiologically dangerous diseases, diseases with a high mortality rate and disability.

On March 6, 2008, the accelerated registration procedure was applied, and a certificate of state registration of the drug Elaprase (Elaprase), intended for long–term treatment of patients with Hunter syndrome - mucopolysaccharidosis type II, was issued. This event is a victory for Snezhana Mitina, who for a long time, stubbornly, daily fighting for the life of her son Pavlik, and all those who helped her in this. It is a landmark for our country, because a medicine for a very rare disease has been registered. Currently, according to the Society of Patients with Mucopolysaccharidosis and the Laboratory of Hereditary Metabolic Diseases of the Medical and Genetic Research Center of the Russian Academy of Medical Sciences, there are about 40 sick children with such a diagnosis in Russia, although based on data on the occurrence of the disease in the population in Russia, there should be at least 150. But, unfortunately, this positive example of accelerated registration is still the exception rather than the rule. For example, children with another type of mucopolysaccharidosis, MPS-1, have been waiting for the drug Aldurazyme for several years. Many of them may simply not need it anymore…

The topic of rare diseases and rarely used medical technologies was raised for the first time in our country in 2005 by the Formulary Committee of the Russian Academy of Medical Sciences, headed by Academician Andrey Ivanovich Vorobyov. In 2006, the Formulary Committee adopted a Temporary Regulation on the procedure for forming a list of rarely used medical technologies, in which it defined the concept of "rarely used medical technology". Medical technologies classified as rarely used should have a high level of proof of effectiveness and vital necessity (without their use in life-threatening diseases and syndromes, the disease will progress or its course will worsen, complications or death of the patient will occur) and rarely be used (the quantitative criterion of rarity is the use (real or predicted) of medical technology less than more than 10,000 people in the Russian Federation). At the same time, a list of rarely used "orphan" medical technologies of the Formulary Committee was first formed and published in the 2nd edition of the Handbook of Medicines of the Formulary Committee (there are only 36 of them in the 2007 edition).

In December 2007, the organization of a Professional Service for Rare and Expensive Diseases was started under the Formulary Committee. The coordinator of the Professional Service is Professor Pavel Andreevich Vorobyov. It is assumed that such a service will have expert and methodological functions and will unite practitioners, researchers, healthcare managers, representatives of patient societies, representatives of pharmaceutical companies, laboratory service specialists, nursing, lawyers, etc. The purpose of its creation is public monitoring of the implementation of the program for 7 diseases (hemophilia, cystic fibrosis, pituitary nanism, Gaucher's disease, myeloid leukemia and other hemoblastoses, multiple sclerosis, condition after organ and (or) tissue transplantation), assessment of the dynamics of the quality of life of patients, their satisfaction with the situation with drug provision and medical care in general, improving the provision of medical and social assistance to patients. Considerable funds have been allocated for the 7 diseases program (about 1 billion euros for 2008), medicines have been purchased twice as much, but the mechanism for bringing a specific drug to each patient has yet to be debugged in practice. Currently, protocols for the management of such patients and the federal register are being created, applications for drugs are being collected and adjusted.

Summing up the above, we can highlight the following main problems currently existing in our country with the provision of medical care to patients with rare diseases:

1. The absence of a capable register of patients with rare diseases (a medical archive is not a register!).
2. The absence of a register of medical institutions that have conditions for the diagnosis and treatment of such diseases and specialists with experience in this field.
3. Lack of high-quality available information and scientific knowledge about rare diseases.
4. Limited or no opportunities for the diagnosis of most rare diseases.
5. The presence of difficulties in accessing treatment, if such exists.
6. Absence of patient management protocols for most diseases.
7. Lack of educational programs for primary care physicians on rare diseases.
8. If there is no diagnosis, registration and protocols for the management of patients, then there is no reason to allocate money from the budget for their treatment.
9. Insufficiently effective, inflexible system of drug provision.
10. The absence of laws regulating the situation with rare diseases and medicines for their treatment.
11. The lack of a working planning system and flexible monitoring of the situation with rare diseases.
12. Insufficient mutual understanding, interaction and coordination between public authorities, medical and social workers and patients.
13. The state does not have the political will to solve this problem, local officials do not have the desire, doctors do not have the ability to solve it, and patients do not have faith that the situation can be changed.

These problems are not unique, they are common to most countries. The only difference is that in other countries they have already begun to solve them, in Russia this problem, from the point of view of officials (civil servants!), as if it does not exist at all.

Part IV. The role of patient organizations in solving the problems of patients with rare diseasesA patient with a rare disease very often finds himself alone with his disease.

His voice is inaudible neither to the public nor to the authorities. His problems seem insignificant against the background of solving global problems. Therefore, a huge role in solving the problems of patients suffering from rare diseases is played by patient organizations, because only by uniting, it is possible to move the situation from a dead point.

The first national organization of patients with rare diseases was established in the USA in 1983 (National Organization for Rare Disorders – NORD). Its founders were patients and their relatives who initiated the adoption and participated in the development of the law on rare diseases and "Orphan Drugs" (Orphan Drug Act) in the United States. The main tasks of NORD are "recognition, treatment and assistance to patients with rare diseases through the implementation of training and research programs, advocacy of their interests and provision of services."

The European Organization of Patients with Rare Diseases (EURORDIS) was established in 1997. It is a non-profit, non-governmental, patient-managed union of organizations and people actively working in the field of rare diseases. The mission of Eurordis is to build a strong pan-European community of organizations of patients and people living with rare diseases, to be their voice at the European level, directly or indirectly to fight against the impact of rare diseases on their lives. Currently, EURORDIS unites more than 320 patient organizations from 19 European countries and represents 29 million patients in the European Union.

There are still isolated patient organizations in Russia. The passivity of patients is caused on the one hand by their limited, first of all, physical capabilities, and on the other by disbelief in the possibility of influencing the existing administrative and bureaucratic state machine and somehow changing their life situation. Currently, only a few organizations are actively working: the All-Russian Charitable Public Organization of Disabled People "All-Russian Society of Hemophilia" (established in 2000), the Interregional Public Organization "Assistance to patients with cystic fibrosis" (established in 1997), the Interregional Public Organization for Assistance to Disabled People from childhood suffering from Gaucher's disease and their Families (established in 2000), the All–Russian Public Organization of Disabled People with Multiple Sclerosis (established in 2001), the Interregional Charitable Public Organization "Society of Disabled People suffering from Hunter syndrome, Other Forms of Mucopolysaccharidosis and Other Rare Genetic Diseases" (established in 2004), the Charitable Foundation "Association of Parents of Disabled Children "Angel" (rare genetic diseases) (established in 2004), non-profit institution "North-Western Society of Patients with Rare Diseases" (established in 2005).

At the beginning of 2008, the National Association of Organizations of Patients with Rare Diseases "Genetics" was established in St. Petersburg. The main goal of the Association is to unite organizations of patients with rare and rare genetic diseases throughout Russia. The main tasks are synchronization and coordination of actions aimed at improving the health and social status of patients; assistance in organizing their treatment, socialization and rehabilitation; attracting the attention of state authorities, local self-government and the general public to the existing problems of patients; preparation of proposals to representative bodies of Russia and the subjects of the Russian Federation aimed at the development and improvement of legislative and legal framework concerning disabled children, their parents and other patients with rare diseases; dissemination of information about the existence of rare diseases, modern possibilities of their diagnosis and treatment; representation and protection of the rights and legitimate interests of patients. In many regions of our country, the parents of sick children and the patients themselves did not know where to start their dialogue with the authorities in defense of their rights, but after receiving support from the Association, they begin to unite for joint actions.

The dialogue between the authorities, organizations of patients and medical institutions is difficult to develop. The format of the relationship "official – doctor – patient" is not familiar to our society. Traditionally, everyone tries to solve the problems themselves, alone, due to their own (often erroneous) understanding and vision of solutions, and as for officials, then with the least effort, time and money. And if the problem is not solved, then "there is no court and there is no court." Each of the participants in the dialogue has its own language, often not understandable to the other, its own way of thinking, its own vision of the situation, its "own" truth. For example, many doctors believe that the patient does not need to provide complete information about his illness. The same opinion is shared by some patients. To come to mutual understanding and joint actions to achieve a common goal, you need to learn to understand each other, and for this you need time and desire.

Currently, attempts to establish a dialogue are already being made. In April 2007, Roszdravnadzor and a number of patient organizations belonging to the "7 nosologies" group concluded an agreement on cooperation in improving the provision of medicines to citizens and information exchanges.

In July 2007, Minister M. Zurabov met with representatives of associations of patient societies: the All-Russian Society of Hemophilia, the interregional public organization "Assistance to patients with Cystic fibrosis", the regional public organization of the disabled "St. Petersburg Society of Epilepsy Sufferers", the public organization "St. Petersburg Diabetic Society of the Disabled", the All-Russian public organization of disabled people with Multiple Sclerosis, interregional public organization "Assistance to disabled people suffering from Gaucher's disease from childhood and their families", autonomous non-profit organization for assistance to patients with oncological and oncohematological diseases "Assistance", interregional public organization of disabled people "Rheumatology Association "Nadezhda". As a result of the meeting, it was decided to create a permanent working group under the Ministry, actively cooperate in the development of treatment standards for these nosologies, updating the register of patients receiving drug therapy, participation of representatives of associations in competitive procedures for the supply of medicines, as well as building competent logistics for the delivery of medicines to the patient.

On January 25, 2008, the head of Roszdravnadzor Nikolay Yurgel signed an Order "On the establishment of public councils under the Offices of Roszdravnadzor in the subjects of the Russian Federation". According to Professor Yurgel, the participation of patients and public associations in discussing the problems of reforming the healthcare system, improving the quality and accessibility of medical care, organizing control and supervision in the healthcare sector is an important element of civil society. "In order for the interaction of state authorities, business, local self-government and public associations to be effective, it must be carried out on a regular basis, based on the principles of voluntariness, professionalism and openness. Only in this case we can count on the creation of a truly effective and patient-friendly healthcare system in the country," the head of Roszdravnadzor stressed.

With a fairly active position of the Ministry of Health and Social Development and Roszdravnadzor at the regional level, there are big problems in establishing a dialogue. The reason for this is the lack of regulatory documents. Most recently, in the Health Committee of the Government of St. Petersburg, we received a response to a proposal to conclude a cooperation agreement with several organizations of patients along the following lines: "The Ministry of Health and Social Development is free to do anything, that's why he and the Ministry of Health and Social Development, and we do not have the authority to do this." At the same time, it should be noted that we have never been denied assistance in resolving situations with specific patients. A similar situation arose in the Medical and Genetic Center. Only in this case, the Chief Geneticist of St. Petersburg forbade (did not recommend) signing any agreements with organizations of patients.

In order to avoid such problems, it is necessary to develop ethical standards for the work of patient organizations, to determine the legal status of organizations representing the interests of patients in interaction with executive authorities; to solve the issue of control by public organizations of patients in the field of circulation of medicines, for the compilation and maintenance of patient lists in the regions and at the federal level, etc.

There is also a real need to organize so-called "patient schools", conduct special trainings in order to provide the patient and his relatives with maximum information about the disease, teach them to correctly assess and perceive the current state of affairs. Simply put – to teach you to live anew in the struggle and at the same time in harmony with the disease. After all, for many patients, especially those who receive effective treatment, it just becomes a special way of life. And it is here that public organizations should also play their special role. This practice has recently become widespread abroad and is proving to be highly effective. For example, it is becoming a good and useful tradition to hold annual summer meetings of families of patients with mucopolysaccharidosis and other rare genetic diseases in Poland. But going abroad is not always convenient for many reasons, both financial and physical. It's time to think about such "survival schools" in Russia.

The first fruits of cooperation between state authorities, doctors and organizations of patients have already been received. This is the inclusion of drugs for the treatment of rare diseases in the federal program since 2005, when drugs for the treatment of cystic fibrosis, hemophilia became really available, since 2006 – Gaucher's disease. This is the beginning of the implementation of the "7 nosologies" program in 2008 (it includes hemophilia, cystic fibrosis, Gaucher disease, multiple sclerosis – 4 out of 7 nosologies). This is the approval of the Regulation on the accelerated procedure of state registration of medicines.

These facts show that the situation can be changed and it needs to be changed! Patients suffering from rare diseases have real hope.

People suffering from rare diseases, unite!

Part V. A very rare day for special peopleFebruary 29, 2008 became the first International Day of Patients with Rare Diseases.

The choice of this date for such an event is not accidental. The 29th day of February happens 1 time in 4 years, which in itself symbolizes the concept of rarity. On this day, hundreds of events dedicated to the problems of patients with rare diseases were organized in many countries of the world (in the European Union, USA, Canada, Croatia, Ukraine, Armenia, Russia, etc.), which caused a huge public outcry. Their purpose was to draw attention to the problems of patients with rare diseases, to raise awareness of rare diseases and their impact on people's lives, to approach an understanding of their importance as a public health priority.

Why was this day held?

Because there are children and adults with rare diseases who urgently need help;

• Because it is necessary to disseminate information about rare diseases among health workers and the population. Information is the basis for improving their living conditions;
• Because a day focused on rare diseases will help keep hope alive for sick people;
• Because funding is needed to solve the social and medical problems of patients and conduct scientific research in this area;
• Because simultaneous coordinated actions around the world can ensure that the voice of patients with rare diseases will be heard;
• Because we need coordination of actions at the national level and in different regions;
• Because rare diseases should become a priority for healthcare today.

In Russia, events dedicated to the International Day of Patients with Rare Diseases were held in Moscow and St. Petersburg.

On February 28, 2008, a press conference on the topic was held in Moscow at the RIA-Novosti news agency: "The first European Day of Rare Diseases". At the press conference, the Certificate of the Professional Service for Rare Nosologies of the Formulary Committee of the Russian Academy of Medical Sciences "The situation with drug provision for patients with 7 rare expensive diseases at the end of February 2008" was published.

In St. Petersburg, the press conference "A very rare day for special people" was held on February 26. It was organized by the National Association of Organizations of Patients with Rare Diseases "Genetics". It was attended by representatives of public organizations of patients with rare diseases, doctors involved in the diagnosis and treatment of such patients, patients with rare diseases and their relatives, representatives of manufacturers of "orphan medicines", representatives of the media. An exhibition of drawings and photographs of children with rare diseases, field seminars in medical and educational institutions of the city was organized. We need to learn how to negotiate, we need to learn how to find ways to solve problems, because there are many problems, and they are being solved, unfortunately, in a fragmentary way.

Part VI. Personalized medicine and treatment of rare diseases as a strategic direction of healthcare development until 2020An open discussion of the Concept of the development of Russian Healthcare until 2020 is, of course, a very important and necessary step.

A few years ago, it was impossible to even dream about it. However, the analysis of the proposals and concepts received at the moment shows the predominance of assessments of the situation that has already developed in healthcare and the introduction of tactical proposals to solve them. But there is really very little strategic planning that takes into account global trends in the development of healthcare, medical and related sciences and fields, but planning is long-term, more than 10 years ahead. There is not a word on the site about rare diseases, although this area has been among the top three priority areas of health development in developed countries for a number of years.

In our opinion, the priority of the concept should be "ensuring fair access to diagnosis, treatment and medical care" for all people, including those suffering from rare diseases.

As the main strategic directions, we offer the following:

1. Increasing knowledge about the epidemiology of rare diseases.
2. Recognition of features of rare diseases.
3. Development of information for patients, healthcare professionals and society in general, which concerns rare diseases.
4. Training of healthcare professionals to improve the diagnosis of rare diseases.
5. Organization of screening, improvement of diagnostics and ensuring its availability.
6. Facilitating patients' access to treatment and quality medical care.
7. Stimulating research and innovation on rare diseases, especially in the field of treatment. Development of new drugs and treatment methods.
8. Realization of the specific needs of people who suffer from rare diseases, improvement of the rehabilitation system.
9. Development of the system of public control in healthcare, support of patient associations.
10. Creating the necessary infrastructure that ensures a clear coordinated work of all components of the healthcare system.
11. Development of national and international cooperation in the field of rare diseases.

To ensure the implementation of the above directions , the immediate tactical tasks should be:

1. Analysis of the situation with the provision of medical and social assistance to patients with rare diseases. Creation of an operational computerized epidemiological surveillance system for rare (and not only) diseases, taking into account their features and diversity. The main element of this system should be the national register of patients with rare diseases, and the register is active, with feedback from patient organizations and individual patients. This will make it possible to combine currently existing disparate databases, quickly accumulate and analyze incoming information, for operational management decision-making and business planning in innovative areas of the national economy related to medicine. The importance of such a system for medicine is equivalent to the importance of building a road network for the entire national economy of the country. If there is no information about the actual occurrence of the disease, it is impossible to assess the need for a particular drug or treatment method, it is difficult, and often almost impossible to attract financial resources for research and commercialization of existing developments.
2. Analysis, calculation and justification of the costs of treatment and social rehabilitation of patients with rare diseases, assessment of their economic feasibility.
3. Creation of a system for monitoring the implementation of drug provision and medical care programs and analysis of their effectiveness.
4. Increasing knowledge about rare diseases for a better understanding of their course, assessing the need for resources and their rational use, tracking the progress of patients in the healthcare system and evaluating the effectiveness of treatment.
5. Raising awareness of society, medical and social workers, patients and their relatives about rare diseases, modern possibilities of diagnosis, therapy and rehabilitation of patients with rare diseases. Creation of Russian-language information resources that provide real-time access to reliable and up-to-date information in this area.
6. Support organizations of patients suffering from rare diseases. Adoption of legislative provisions regulating their relations with medical, social institutions and public authorities.
7. Creation of databases of medical and social institutions (as well as individual specialists) with the capabilities and experience of treatment and rehabilitation of certain rare diseases, where, if necessary, patients could be referred for consultation and medical and social assistance.
8. Development and implementation of national protocols and standards for the diagnosis, treatment and monitoring of rare diseases and conditions.
9. Development of training programs on rare diseases. Introduction of the topic "rare diseases" in the training programs of narrow specialists. Organization of postgraduate medical education in rare diseases.
10. Expansion and improvement of the organization of screening programs for rare diseases (population screening: prenatal, neonatal, adult; targeted screening).
11. Increasing the availability of diagnostic studies by creating new and/or improving the equipment of existing laboratories in federal districts and subjects of the Russian Federation.
12. Creation of networks for the provision of medical and medico-social assistance to patients with rare diseases, starting with advisory centers in the subjects of the Russian Federation with the general coordination of their work by leading research institutes. Endowment of advisory centers with expert powers. Ensuring that these centers fulfill the role of a source of information for patients and their families.
13. Creation in the Ministry of Health and Social Development and health management bodies of the subjects of the Russian Federation of separate units engaged in the organization of medical care for patients with rare diseases and the prompt solution of their problems, as well as working groups on individual diseases, including representatives of the Ministry, doctors with experience in the treatment of such patients and representatives of organizations of patients.
14. Ensuring coordination between public authorities, healthcare, social protection and education institutions, manufacturers and suppliers of medical products and public organizations in the field of state policy concerning the treatment and social protection of patients with rare diseases by creating coordination councils at the federal level and in the subjects of the Russian Federation.
15. Coordination and provision of state support for scientific research in the field of diagnosis and treatment of rare diseases.
16. Adoption of a package of laws regulating activities in the field of rare diseases and rare medical technologies.
17. Joining the work of international bodies: the World Health Organization, relevant committees and commissions of the European Union on the development of nomenclature and classification adapted for rare diseases.

Of course, these proposals are, so to speak, a draft version of the program, they need careful discussion, elaboration, evaluation and superstructure. But as for any new project, a starting point is needed, and then the key to success will be the purposeful and hard work of all stakeholders and target groups. And we hope that all of the above and the above will become such a point and will help bring domestic healthcare to the forefront.

Why should personalized medicine, detection and treatment of rare diseases become one of the main priorities for the development of healthcare in our country?

1. Because the development of this direction is a global trend. We have come to a certain stage in the development of society, when it became necessary to move from mass treatment to individual treatment. All developed countries have gone through this.
2. Because for the treatment of an increasing number of previously incurable diseases, new medicines or treatment methods are emerging that allow patients to either become absolutely healthy people, or, if not healthy, then at least feel healthy and be socially adapted in life.
3. Because early detection and timely treatment of a rare disease often allows you to save a lot of money due to the needlessness of expensive treatment in the later stages of the disease, by reducing the cost of maintenance and rehabilitation of the patient, the absence of long-term disability payments, disability payments to the patient and his relatives. In many cases, a person has the opportunity to remain a full-fledged member of society, to benefit him with his work, to create material, intellectual, cultural and other values.
4. Because according to Article 41.1 of the Constitution of the Russian Federation, "Everyone has the right to health protection and medical care" ... regardless of the frequency of his disease.
5. Because according to Article 17 of the Fundamentals of the Legislation of the Russian Federation on the Protection of Citizens' Health (Federal Law No. 122-FZ of August 22, 2004), "The State provides citizens with health protection regardless of gender, race, nationality, language, social origin, official position, place of residence, attitude to religion, beliefs, belonging to public associations, as well as other circumstances. The State guarantees citizens protection from any form of discrimination caused by the presence of any diseases."
6. Because this direction is in tune with the foundations of the worldview of the Russian medical school, laid down by S.P. Botkin.
7. Because rare diseases pose a political problem in its noblest sense: to take into account the needs of the weakest and smallest group of the population. If we want to guarantee equal access to treatment, if we achieve the highest quality of care and support, it is obvious that this problem requires a change in the entire health and medical and social care system.
8. Because the development of approaches to the diagnosis and treatment of rare diseases is one of the main sources of innovation in medicine. The experience of creating "orphan drugs" for the treatment of rare diseases will allow in the future to apply developments in the field of biotechnology, tissue and genetic engineering for the treatment of an increasing number of diseases, including common ones.
9. Because this direction can be a point of growth, an indicator of the improvement and efficiency of the health care system.
10. Because it can be an incentive to the development of domestic pharmacy, bio– and nanotechnology, genetics and other areas of the national economy. Without its development, it is difficult to create an effective system for the introduction (commercialization) of innovative developments in the field of medicine.

Taking into account all factors, rare diseases should become one of the priority directions of the development of domestic medicine for the period up to 2020. This area is certainly of strategic, infrastructural and systemic importance. Thanks to its development, there will be a good chance to achieve visible progress in the health and life expectancy of the population by 2020. The most important thing is not to stick your head in the sand like an ostrich and not to avoid solving problems, but to work systematically and persistently on them. And then the result will not keep you waiting.

Portal "Eternal youth" http://vechnayamolodost.ru15.02.2010