Pharmaceutical production in Russia: to the bottom, and then...

"Man and Medicine" – 2010. Part 2.
The country's drug independence in the prism of the patient's drug safety:
problems and priorities, strategies and tactics of the Russian FederationF.
Snegirev, "Weekly Pharmacy", 03.05.2010

During the plenary session of the XVII Russian National Congress "Man and Medicine", held on April 12-16, 2010 in Moscow, Vladimir Petrov, Academician and member of the Presidium of the Russian Academy of Medical Sciences, Professor, Doctor of Medicine, Honored Scientist of the Russian Federation, Honored Doctor of the Russian Federation, Rector of Volgograd State Medical University (VSMU), Head of the Department of Clinical Pharmacology, spoke and intensive care. In his report on the topic "The creation of new domestic innovative medicines as the basis of drug safety in Russia", he resolutely rejected doubts about the need to specify state guarantees in the field of drug provision, where, in addition to the purely medical component, the economic accessibility of medicines for the population is of great importance (which is certainly important not only in the conditions of financial crisis).

The research cycle of drugs is well known to all pharmacologists and pharmacists: the birth of a new drug is based on fundamental research (for more information, see the previous article, "Medicine and Mathematics – achievements and prospects"), and without special attention (funding) from the government, leaders of the pharmaceutical industry, various organizations and foundations, conducting these studies, essentially impossible. To create new drugs, it is necessary to perform tasks arising from a deep understanding of pathological processes — this is possible in clinics that have in their ranks not only practitioners engaged in direct medical care, but also scientists developing knowledge about the disease. Such knowledge cannot be obtained without performing applied research in the clinic, providing information about the effectiveness and safety of treatment. This happens as a result of conducting, analyzing and comprehending clinical studies and meta—analyses: comparing treatment methods, specialists can choose the most effective and safe of them, which should form the basis of medical care and its standards (currently, the Russian Federation is actively working on new standards of drug care).

Medicines are like people: they are born, live, leave the stage. They're dying. Upon completion of the research, a new drug is obtained; with the expiration of its patent protection, generic drugs appear on the market that begin to compete against the original drug. Children are against fathers. It would be difficult to welcome such processes if it were not for the fact that "children" are more accessible to the broad masses of the population and, accordingly, are used more widely, saving people and ensuring the quality of life of patients. Further, new generics appear on the market, marking a new stage of competition – this time between generics: high-quality and not so much. Competition leads to lower prices, which allows all citizens of the community to receive proper treatment (including in the conditions of compulsory medical insurance). And then comes the next stage: analysis and disappointment. According to the speaker, this applies to almost all drugs. Insufficient power and breadth of therapeutic effects on the one hand and a significant number of adverse reactions on the other require the creation of new drugs. As you know, the financial and time costs averaged around the world for the creation, from development to implementation, of an original drug - one active pharmaceutical ingredient (API) of 8-10 thousand molecules – are calculated over a period of 15 years of life and an amount of 1 billion US dollars. According to V. Petrov, in Russia today there are real conditions and opportunities to reduce the time and cost of drug development – for this it is proposed to take a number of steps. The country has adopted a Strategy for the development of the Pharmaceutical industry of the Russian Federation for the period up to 2020, approved by Order No. 965 of the Ministry of Industry and Trade of the Russian Federation dated 23.10.2009;. This document assumes certain amounts and sources of financing; in total, 177,620 million rubles are provided for the period 2009-2020 (in February 2009 prices), including in the following areas:

• Professional development of personnel and creation of infrastructure – 35,220 million rubles.;
• Transition to GMP – 36,000 million rubles.;
• Development of medicines – 106,400 million rubles.

Of course, these funds are clearly insufficient, but they have appeared for the first time within the framework of state support," the speaker noted.

According to the principle of chronology of implementation , the main activities for the implementation of the Strategy are divided into three groups:

• until 2013 – placement of high-tech pharmaceutical industries on the territory of the Russian Federation;
• until 2017 – the introduction of generic import substitution, the acquisition of appropriate licenses and ensuring the country's drug independence;
• until 2020 – development of innovative drugs – analogues of products under patent protection; development of innovative drugs that have no analogues.

The main goal of the state policy of the Russian Federation for the development of the national pharmaceutical industry for the period up to 2020 is to create conditions for its transition to an innovative development model, which should lead to an increase in the provision of the population and healthcare institutions with drugs of domestic production, with a general increase in the provision of medicines to the average European level both in quantitative and qualitative indicators. Among the expected results of the Strategy implementation are:

• increasing the share of domestic products in the total volume of consumption in the domestic market to 50% in value terms by 2020.;
• changes in the nomenclature of drugs produced in the territory of the Russian Federation, including an increase in the share of innovative drugs in the portfolios of local manufacturers to 60% in value terms;
• the increase in exports of pharmaceutical products by 8 times compared to 2008.;
  ensuring drug safety of the Russian Federation according to the nomenclature of strategically important drugs and vaccines;
• stimulation of the organization of production of pharmaceutical substances in the territory of the Russian Federation in the amount necessary to ensure the release of 50% of finished drugs in monetary terms, including at least 85% of the nomenclature from the List of vital (essential) medicines (VED).

(As of January 2010, the List of VED is valid, approved by the Decree of the Government of the Russian Federation No. 2135-r dated 30.12.2009. This List is formed using the WHO international Anatomical Therapeutic and chemical classification system, Anatomical Therapeutic Chemical (ATS) classification system, and includes 500 positions of drugs under international nonproprietary names.)

The implementation of the main activities of the Strategy and obtaining the expected results provides for three main stages:

1. Localization of production and development of drugs in the territory of the Russian Federation;
2. Development of the pharmaceutical industry in the Russian market;
3. Development of the Russian pharmaceutical industry in foreign markets.

It may seem like "good intentions" to someone, but they are already beginning to be realized," V. Petrov stressed. – In the development of the modern pharmaceutical industry, two main trends of its saturation and formation prevail: innovative drugs (original developments) and generic drugs. Both of these areas are important – and each in its own way. At the same time, it is necessary to understand that own innovative drugs are expensive, but foreign ones will be more expensive. After all, original developments are golden eggs laid by a chicken: it is only important to grow this chicken together and not let it go under the knife. Meanwhile, the generic vector is a well–known and reliable way to save money in any state of the world: the use of such drugs allows you to provide proper medical (pharmacotherapeutic) care to all segments of the population.

So does Russia have its own innovative developments? It is known that new drugs are created primarily on the basis of new molecules. For example, the U.S. Food and Drug Administration registers about 20 new molecules annually. Recently, the press, the media and other tribunes of various ranks have often heard the thesis that there is nothing new in Russia and nothing has been created for a long time. According to V. Petrov, the grounds for such statements, alas, are not groundless – however, such a reproach is only partially true. As long as innovative products are not in demand and provided with effective demand, their market share will be negligible. This means that Russian domestic developments will still remain the exception rather than the rule. At the same time, the Russian Federation has both modern scientific, technological and production facilities, as well as its own unique drugs. There are niches in which Russian scientists and specialists have achieved significant success, for example, immunology and virology, which are still advanced in terms of both scientific and industrial potential. The speaker recalled how quickly Russia was able to offer the whole world a vaccine against avian influenza and even the pandemic H1N1 influenza strain – and these vaccines are purchased by many countries of the world, including the United States. But first of all we need to provide for ourselves. The speaker also recalled the first Russian growth hormone preparation, the technology of which was developed by scientists of the Institute of Bioorganic Chemistry of the Russian Academy of Sciences named after M.M. Shemyakin and Yu.A. Ovchinnikov; in the same scientific institution, a group of scientists led by Academician of the Russian Academy of Sciences A.I. Miroshnikov developed an original Russian technology for the production of granulocyte colony stimulating factor. In Ufa (at the Farmstandart-Ufavita enterprise), insulins and a growth hormone preparation (Rastan) are produced, which belong to the field of high technologies and have good prospects not only in solving the problems facing Russian healthcare, but also in terms of export potential. Today, the drug Arbidol (developed in the Soviet Union by the joint efforts of scientists of the All-Union Research Chemical and Pharmaceutical Institute, the Medical Radiological Research Center of the Russian Academy of Medical Sciences (Obninsk) and the Leningrad Research Institute of Epidemiology and Microbiology named after L. Pasteur) leads in sales among antiviral agents and drugs for the treatment of acute respiratory diseases, adequately competing with well-known foreign brands of this group in the Russian and foreign pharmaceutical markets.

The experience of effective interaction between the scientific sector and pharmaceutical production exists in the Volgograd Pharmacological cluster being created: the result of innovative research projects was the creation of drugs such as Asparkam L solution for infusions, Asparkam L solution for intravenous administration, Magnesium Pyridoxine (a combination of L-asparaginase with pyridoxine) – those drugs that can replace many foreign means for treatment of cardiovascular pathology containing Mg⁺⁺ and K⁺ cations. Combining the research potential of university science with the capacities of the Russian pharmaceutical company Materia Medica made it possible to create, test and bring to market 9 fundamentally new, effective and safe drugs for the treatment of socially significant diseases that contain antibodies to various receptors. Among such antiviral agents are immunomodulators, interferon inducers (which are registered not as homeopathic, but as full-fledged allopathic drugs) Anaferon, which in the course of multicenter studies has demonstrated high efficacy in the treatment of influenza and ARVI (including in pediatric practice), is included in the Russian national List of VED. Also, VSMU scientists have developed a new oral antihyperglycemic drug diabenol (imidazole derivative): at one time, the main funds for the development of diabenol were received within the framework of state programs, and grant funds accounted for only a small part of the investment – in this regard, V. Petrov stressed the importance of state programs supported by funding as an important mechanism for solving socially significant tasks.

How to expand advanced trends and strengthen the country's pharmacosafety? The proposals of the Problem Commission on Clinical Pharmacology of Metabolism of the Russian Academy of Medical Sciences, headed by the speaker, are reduced to (through the newly created expert council) once again identify priority areas, in particular:

• population drug prevention and therapy: cheap, effective, safe drugs for the prevention and treatment of cardiovascular diseases, diabetes mellitus, viral infections, etc.).
• creation of poly-pill: combinations of an angiotensin converting enzyme inhibitor, statin and acetylsalicylic acid in one tablet – these three drugs must be combined in one tablet (other recommendations are possible).

First, it is necessary to conduct an expert assessment, make a rigorous audit and put into practice the existing Russian developments; and then combine in a single scientific and production cycle the process of research in Russian research centers and production at large pharmaceutical enterprises. In order to solve the tasks set, a number of possible (and necessary, in the speaker's opinion) concrete steps and solutions were put forward for consideration, for example:

• legislatively prohibit the registration of new generics in the presence of a generic drug of Russian production (subject to the mandatory condition of strengthening quality control of the Russian manufacturer);
• exclude foreign drugs from the restrictive lists in the presence of a Russian generic (subject to the mandatory fulfillment of the same condition).

The main systemic problems of the pharmaceutical industry include:

• imbalance of regulatory requirements for domestic and foreign manufacturing enterprises;
• economic demotivation of domestic producers;
• shortage of highly qualified personnel for the pharmaceutical industry;
• lack of mechanisms for financing drug development;
• insufficient level of Russian patent legislation and law enforcement practice regarding international standards;
• the absence of mandatory rules for the production and quality control of medicines identical to the international GMP rules (Egorov V.M., 2009).

Among the unresolved problems remains the fact that the development of innovative medicines requires direct investment in research centers, and not indirectly through pharmaceutical production. Without investing in fundamental science today, you will not get the results of applied research tomorrow; without building laboratories, without updating equipment, without purchasing reagents for fundamental research, you will take away tomorrow's discoveries from the country and not allow it to raise its own scientists capable of developing science in production. The state should take on some of the risks, while it is important to invest in teams that provide competitive scientific products. Russia is big. And Moscow is not the whole of Russia: it is strong in the regions with their wonderful heads. After all, if regional research centers are not developed, bright heads begin to look for other activities that can somehow feed them. It is no secret that in the current world practice, manufacturers buy an idea – a molecule, a composition – from researchers and laboratories, investing in promising projects that have already been worked out. Molecules are born not in production, but in the silence of scientific laboratories equipped with personnel that nascent Russian manufacturers cannot afford. Conclusion – the support of the scientific sector is needed. In conclusion, Academician V. Petrov expressed his deep conviction that pharmaceutical manufacturers should not engage in either clinical or preclinical research of new developments – they should delegate this part of their activities to scientists (by outsourcing to certified research institutes and clinics), which will strengthen the scientific potential of the country, improve the quality of research. So – on the way from basic research to knowledge about pathology and further to the results of applied research – specialists will receive the desired goal: an effective and safe medicine. Thus, the pharmaceutical industry, which is one of the most important elements of the healthcare system of the Russian Federation, is on the verge of radical transformations associated with the formation of an innovative component, the development of import substitution and labor productivity growth. The ultimate goal of all these initiatives is to create a sustainable national industry capable of providing the country's population with affordable, effective and safe medicines in the necessary quantities, including a new generation of innovative medicines.

In this context, a report on the topic "The state and prospects of ensuring the quality, effectiveness and safety of medicines in the territory of the Russian Federation", which was delivered by Natalia Bunyatyan, Deputy Director General for Scientific Work of the Federal State Institution "Scientific Center for Expertise of Medical Products" (FSU "NCESMP"), aroused considerable interest of the audience Roszdravnadzor, Doctor of Pharmaceutical Sciences, Professor. Control and supervision is the most important tool for ensuring the modernization of healthcare and the social sphere (Telnova E.A., 2010). Today, serious changes are coming in the Russian pharmaceutical industry, and first of all, in the field of drug provision. March 31, 2010 The Federation Council approved the draft federal law "On Circulation of Medicines": after the bill is signed by the President, the document should enter into force on September 1, 2010. The speaker gave three basic definitions that have already been reflected in the draft law:

• the quality of the drug is the compliance of the drug with the requirements of the federal law or other regulatory documentation;
• drug safety is a characteristic of drugs based on a comparative analysis of its effectiveness and the risk of harm to health;
• the effectiveness of drugs is a characteristic of the degree of positive effect of the drug on the course, duration of the disease or its prevention, rehabilitation, preservation, prevention or termination of pregnancy.

According to Roszdravnadzor, as of 01.01.2010, a total of 18,635 names of ready-made drugs were registered in the Russian Federation, of which:

• domestic production – 12,871 (69%),
• foreign production – 5764 (31%),
• original HP – 1383 (7.4%),
• generic drugs – 17,252 (92.6%).

The structure of the modern pharmaceutical market of the Russian Federation significantly differs from the markets of developed countries in the direction of the predominance of branded generic drugs, in which the substance has escaped patent protection, but trade names are actively promoted. As a result (taking into account the fact that Russia has the longest patent protection period of all possible – 20 years), in practice, consumers often overpay for obsolete drugs under all new trade names. The current system of drug promotion encourages manufacturers to invest heavily primarily in marketing and advertising, and not in the development of new effective and modern drugs (according to the famous American surgeon Will Rogers, "if advertisers spent on improving their products the money they spend on advertising, their products would not need advertising"). At the same time, advertising of prescription drugs for the consumer is prohibited by law, but there are more than 1.5 thousand dispensed without a doctor's prescription: on this occasion (is it worth providing such a significant range of medicines in the hands of a pharmacist, and sometimes, alas, a pharmacist outside the medical control of taking these drugs), industry leaders also face a serious question. A significant number of imported products in the pharmaceutical market and the overwhelming prevalence of its generic sector are strategic problems of the country: it is easy to disarm it in the context of drug independence. These facts do not support the country's readiness to ensure full protection of the most expensive wealth of the state – the health of every member of society by providing safe and effective pharmacotherapy – and at the same time not to depend on foreign countries.

The speaker recalled the metaphor of the luminary of Russian pharmacology M.D. Mashkovsky (1908-2002), expressed by him in one of his last reports in the framework of the congress "Man and Medicine" (2002): "Today we live in the jungle of medicines." After all, the pharmaceutical industry of the Soviet Union almost completely provided its citizens with its own medicines. And today, in order to get the situation back on track (which is what the Strategy adopted by the government is aimed at), a lot of things have to start from scratch. Today, Russia largely depends not only on imported drugs, but also on APIs: their production volume in the Russian Federation has decreased by more than 20 times. If earlier the majority of APIs were produced in the USSR (back in 1992, 272 API names were produced in Russia that met the needs of the production of finished preparations: in different groups from 70 to 100%); a significant part of the substances were exported to the COMECON countries, then since the early 1990s about 90% of them were imported, moreover, up to 70% of them are supplied from China and India. As a result, many domestic enterprises have turned into packing factories that produce the same type of products that have been outdated for decades, often with a low market value. According to the Strategy, stimulating the organization of the production of substances is necessary to ensure the release of at least half of the preparations of finished dosage forms (including at least 85% of the nomenclature of the list of VED), – in general, according to long-term goals, the volume of the Russian pharmaceutical market by 2020 will reach 1.5 trillion rubles.

According to the current legislation, all pharmaceutical enterprises in Russia must switch to international GMP standards by January 1, 2014. In the near future, the Government of the Russian Federation intends to approve the GMP rules and the terms of entry into force of specific requirements of these rules, including the conditions for certification of authorized persons. The deadlines for the adoption of these documents are synchronized with the date of entry into force of the law on the circulation of medicines (September 1, 2010). At the same time, according to the leadership of the Ministry of Health and Social Development of the Russian Federation, when switching to international GMP standards, support for domestic pharmaceutical manufacturers should not be prioritized: such a traditional priority as support for domestic production cannot be dominant in due to its considerable blurriness. On the contrary, priorities have been chosen that meet the interests of the patient and are aimed at providing appropriate medical care: improving the quality of medicines with a reliable assessment of their quality and safety. It is possible to achieve this if we ensure the standard of production processes, in which the product is produced with the same quality indicators from batch to batch.

According to Roszdravnadzor, about 10% of Russian pharmaceutical enterprises have already switched to GMP standards, 40% have separate workshops operating under the GMP system, 50% have not even started switching to GMP standards. At the same time, by the end of 2010, modern laboratories for drug quality control will be opened in each federal district. Currently, such a laboratory is already operating in Gudermes; in June, a laboratory will open in Khabarovsk, in July – in Rostov-on-Don. As of April 1, 2010, 460 enterprises produce drugs in the Russian Federation. Most of these productions are in the Central Federal District, as well as the Volga and North-Western Federal Districts. Of the 460 enterprises, 63 have a state form of ownership. According to the State Statistics Committee of the Russian Federation, the volume of production of pharmaceutical enterprises in the Russian Federation in 2009 amounted to 95.6 billion rubles (in 2008 – 74.8 billion rubles), which indicates a high growth rate of the volume of Russian pharmaceutical production.

Ensuring the effectiveness and safety of drugs is achieved by assessing the quality at all stages of its life cycle. The main role in assessing the quality, effectiveness and safety of medicines is assigned to API (chemical modification, particle size, crystal shape, polymorphism, etc.). Monitoring of the quality of drugs is aimed at preventing the ingress and timely withdrawal from circulation of falsified and substandard drugs, taking into account the information database of Roszdravnadzor (Table 1).

The basic principles of the concept of state quality control, efficiency and safety of medicines were presented and supported at a meeting of the Government of the Russian Federation in June 2008. (Kursk). The fundamental document in the quality control of medicines is the State Pharmacopoeia (GF):

• in 2007, the first part of the GF XII edition was published, harmonized with the requirements of the European Pharmacopoeia and devoted to the description of methods of drug analysis;
• In 2009, the 2nd and 3rd parts of the GF XII edition were prepared and submitted for approval to Roszdravnadzor.

The system of state control over the quality, efficiency and safety of medicines includes:

• pharmaceutical expertise – examination of the quality of drugs at the registration stage;
• preliminary state control – confirmation of compliance with the quality of medicines at the stage of launching into industrial production or before the start of import into the Russian Federation;
• selective and repeated selective state control – examination of the quality of medicines at the stage of treatment;
• pharmacovigilance – identification, evaluation and prevention of adverse reactions (PR) or other possible problems associated with pharmacotherapy.

The number of expert organizations that carry out state control in the territory of the Russian Federation includes: 84 testing laboratories accredited for technical competence and independence; 22 testing laboratories of commercial and departmental organizations; 50 quality control centers of the subjects of the Russian Federation; 2 Federal State Institution of Roszdravnadzor and 10 branches of the Federal State Institution. In October 2007 on the basis of the Federal State Institution "NCESMP" of Roszdravnadzor, a Federal Center for Monitoring the Safety of Medicines has been established, which has been delegated the authority to monitor the safety of medicines and expert assessment of facts and circumstances that threaten people's lives and health (Table 2).

The system is based on state control over the circulation of medicines, primarily through the creation of laboratories in each federal district under the jurisdiction of Roszdravnadzor. A similar network of official laboratories for the quality of medical products – Official Medicines Control Laboratories (OMCL) – was founded in 1994 by the European Directorate for Quality Control of Medical Products (European Directorate for the Quality of Medicines) Council of Europe. The creation of a regional network of expert laboratories in the federal districts of the Russian Federation according to the OMCL type will minimize the entry of counterfeit and substandard products into the drug market, which will have a positive impact on the quality control system of drugs in circulation.

Many steps on this path have already been taken. So, in 2009, Roszdravnadzor completed a pilot project on the introduction of near-infrared spectrometry (BIC method) as a non-destructive express method of quality control and monitoring of drugs; 3 mobile express laboratories were equipped. A library of BIC spectra has been created, including 3,300 spectra of 127 drug names (by the middle of this year it is planned to expand the spectrum bank to 600 names). A screening of the quality of drugs was carried out in pharmacies in Moscow, the Chechen Republic, and the Stavropol Territory – further work of mobile express laboratories is planned in all federal districts of the Russian Federation with the start of commissioning of laboratory complexes.

To be continued.

Portal "Eternal youth" http://vechnayamolodost.ru06.05.2010