FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology

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Vol 14, No 4 (2021)


451-461 462

Background. New pathogenetic treatment options, such as gene therapy, are now used to treat previously uncurable diseases. However, price of such treatment is high, especially in the case of orphan diseases, where costs may many-fold exceed the prices for other types of medication. This raises a question of optimal way of financing gene therapy in Russia.
Objective: to evaluate economic consequences of centralizing procurement of gene therapy in 2021–2030 in the case of the drug indicated for treatment of biallelic RPE65 mutation-associated retinal dystrophy.
Material and methods. Voretigene neparvovec is a new gene therapy that is used to treat RPE65 mutation-associated Leber congenital amaurosis and isolated retinitis pigmentosa. We estimated the number of patients (children and adults) that could be treated with voretigene neparvovec in 2021–2030 in Russia using demographic forecasting method, literature and expert data. Budget costs of treatment were estimated for two scenarios: status-quo, where gene therapy is purchased by regions for higher price, and centralized scenario with federal procurements and lower price for the drug.
Results. Up to 100 children and 56 adults could be treated with voretigene neparvovec in 2021–2030 in Russia. Centralizing procurements at the expense of federal budget may save up to 20.7% or 1.8 billion rub. (1.13 billion rub. for children and 0.67 billion rub. for adults), compared to regional procurements.
Conclusion. Centralizing procurements of expensive drugs intended for gene therapy of orphan diseases may save budget costs of the Russian Federation, compared to status-quo decentralized purchases.

462-467 316

Objective: To study the evolution of consumption of antithrombotic drugs used for the treatment of atrial fibrillation (AF) at the outpatient stage in the Saratov Region using the ATC/DDD (Anatomical Therapeutic Chemical Classification / Defined Daily Doses) and drug utilization 90% (DU90%) analysis.
Material and methods. We analyzed the outpatient stage of treatment using the data reflected in 511 case histories of AF patients hospitalized in specialized cardiology departments of the Saratov Region in 2011–2018. The study of the consumption volumes of antithrombotic drugs was carried out using the ATC/DDD- and DU90%-analysis methodology. The consumption of drugs with proven efficacy in AF was expressed as the number of daily doses (NDDD) per 1000 AF patients per day.
Results. In 2011, the number of prescribed DDD of oral anticoagulants (OACs) was 5.29 NDDD per 1000 AF patients per day, and all of them were represented by warfarin; in 2018, this indicator increased up to 277.51 NDDD per 1000 AF patients per day, of which direct OACs amounted to 237.06. The consumption of antiplatelet agents remained at a high level, and in 2018, was 582.53 NDDD per 1000 AF patients per day. Acetylsalicylic acid was included in the group of drugs accounting for 90% of all antithrombotic drugs at the outpatient stage – 99.02% in 2011, 93.08% in 2012, 58.55% in 2016, 60.27% in 2017, and 46.66% in 2018.
Conclusion. The consumption volumes of OACs used at the outpatient stage of treatment of AF in the Saratov Region increased significantly in the period from 2011 to 2018, mainly due to direct OACs. At the same time, the consumption volumes of antiplatelet agents remained at a high level.

468-479 380

Objective: identification of peptides in the composition of Laennec®, which can inhibit the development of endotheliopathy (endothelial dysfunction).
Material and methods. Hybrid mass spectrometry followed by data analysis based on topological recognition theory was performed. The analysis of the peptide composition of Laennec® included four stages: purification of the drug, chromatographic separation of peptides, determination of the multidimensional mass spectrum of the peptide fraction, and de novo sequencing of the isolated peptides.
Results. The preparation contains peptides-inhibitors of specific target proteins (PRKCZ, PKB, PKD1, MAPK14, IKKB, PDPK1) involved in the activation of the pro-inflammatory transcription factor NF-κB. Inhibition of CDK5 and SHC1 kinases helps to reduce endothelial cell apoptosis. The peptides of the drug also block enzymes involved in the synthesis and maturation of the tumor necrosis factor alpha (MAPKAPK2/3, ADAM17).
Conclusion. In the composition of Laennec®, peptides have been found that contribute to a complex pathogenetic action against endotheliopathy. Endothelial regeneration is especially important in the rehabilitation of patients who have recovered from COVID-19.

480-492 390

Objective: to study the potential for the development of financing the Compulsory Health Insurance (CHI) system in Russia.
Material and methods. Оur research estimates the amount of funds available in the CHI system based on fractal analysis and ARIMA modeling. The proposed approach makes it possible to determine the critical amount of funds in the CHI system. Once the limit is reached, the chance of violating the economic security requirements will increase.
Results. Аn increase in the volume of available funds in the CHI sector is expected in the mid-term perspective on the verge of quarter 1, 2023. The amount of funds required to pay for medical care for the respective period of time will increase by 0.77% quarterly.
Conclusion. Gaining additional funds might be possible by optimizing the internal networks for generating cash flows in the CHI system, as well as applying additional ways of financing medical care (particularly Voluntary Health Insurance policies). It would be practical to redistribute the functions of financing health care between the Federal Fund for CHI and its territorial branches. It is essential to review the role of health insurance companies in monitoring the health care quality by improving the communication with citizens.

493-514 316

Objective: to study features of intellectual property protection mechanisms on the example of drugs for the treatment of rare (orphan) diseases.
Material and methods. Analysis of pharmaceutical market data was performed with the DSM Group analytical database. The approach proposed by the Russian Federal Industrial Property Service was used for creating patent landscape. The method supposes conducting a patent search and analysis of the documents found for date of filing, office (country) of filing, applicant, as well as analysis of the patent activity (dynamics) for the subject, in this case, for orphan drugs having a defined structure.
Results. We proposed the complex conclusions to increase national drug safety. Intellectual property limitations for importing countries such as data exclusivity, do not allow to reproduce clinical trials, which leads to non-disclosure of medical data to all parties – medical society and patients, all other market participants, including local pharmaceutical producers. Current intellectual property restrictions conceal crucial data from medical and patient society and other market players and affect accuracy of diagnosis and treatment. Along with outstanding cost of new therapies it causes enormous budget burden for the healthcare system and prevents the introduction of objective criteria in the appointment and use of medicines. Prior to the approval and submission of the registration certificate by the regulatory authority, it is necessary to establish reasonable marginal prices, to form a sufficient set and volume of clinical guidelines and to determine in advance the sources of financing and mechanisms of integration into the national system of drug provision.
Conclusion. The introduction of drugs for the treatment of rare diseases into circulation leads to a sharp increase in the burden on the budgets of the healthcare system at all levels. Current restrictions and obligations in the field of intellectual property rights protection, the degree of disclosure of medical data in the process of registration and admission to the market require significant changes to the traditional system of drug provision and the system of placing state orders, as well as the introduction of new regulatory mechanisms (for example, compulsory licensing or producing individual dosage forms in pharmacy organizations), contributing to the development of the local pharmaceutical industry and providing the national health system with the necessary volume of drugs with a sufficient level of quality and safety.

515-522 293

Background. Specific features of medical products (MPs), their active development and implementation in healthcare require post-market control and safe use.
Objective: to study the existing state regulation in the field of medical products, methods of state control, self-control in medical organisations for their use.
Material and methods. Regulatory legal acts of the Russian Federation defining mandatory requirements, control over the use of MPs were analyzed. Indicators of Federal Service for Surveillance in Healthcare (Roszdravnadzor) in this area were studied. A survey of medical professionals on the safe use of MPs was conducted, the answers of 343 respondents were evaluated.
Results. The analysis of regulatory legal acts shows that, unlike with medicines, biomedical cellular products, when it comes to MPs application requirements, methods of use are not sufficiently specified. State control over the circulation of MPs is generally structured and regulated. The main ways of modern state control are the introduction of a risk-oriented approach to conducting scheduled inspections since 2018, the introduction of a mechanism to control purchases of medical services and products. Typical violations identified by Roszdravnadzor in medical organisations are the use of unregistered or substandard MPs. Also, a frequent violation is a failure to report (or untimely communication) to Roszdravnadzor about undesirable reactions when using MPs. State regulator has developed and approved a mandatory procedure for internal control of quality and safety of medical practice, including control over the storage and use of MPs. At the same time, according to the results of the survey, managers are not sufficiently informed on where to take up-to-date information that the MPs need to be stopped using. Additionally, the survey confirmed that representatives of medical organizations administrations know less than doctors about poor quality MPs in the clinic. Another finding of the survey was that the frequency of unwanted reactions to the application of MPs is significant, but the amount of reporting to the regulator is insufficient. This situation increases the risk of harm to the life and health of patients. In addition, there is a significant frequency of incidents in the use of MPs, with very little reporting to Roszdravnadzor from medical organizations.
Conclusion. Further improvement of regulation in the field of MPs circulation at the post-registration stage, strengthening of control, primarily internal, over their safe and effective use are necessary.


523-536 340

Background. The spread of chronic viral hepatitis C (CVHC) among the population entails significant costs for society, both direct, associated with the treatment of such patients, and indirect, associated with the shortfall in fiscal payments to the budget, due to the disability of this category of patients. Therefore, an important task remains to assess the global economic burden of the disease, taking into account the pathological conditions of the human body associated with it.
Objective: to systematize studies of published sources devoted to assessing the global economic burden of chronic viral hepatitis C.
Material and methods. A feature of the proposed review design is paying attention not only to the objects of assessment under study, but also to the instrumental (including mathematical) means of scenario assessment of the global burden. The study analyzed 29 sources published between 2014 and 2020 and dedicated to assessing and forecasting the global economic burden of CVHC both in individual countries and continents as a whole, and in individual regions of countries. The main criterion for the selection of studies was the availability of an estimate of the global burden of CVHC, taking into account the use of direct antiviral drugs for the treatment of hepatitis C. The search was conducted in PubMed/MEDLINE and eLibrary databases, and in the ResearchGate network.
Results. Of the 29 analyzed sources, 40% of the works consider the burden for CVHC only of certain genotypes; in the overwhelming number of articles (80%), when assessing the burden, the distribution of patients by the degree of liver fibrosis is taken into account. In 50% of the studies reviewed, quality of life adjustment tools (QALY or DALY) were used to estimate the global economic burden. A third of the publications took into account both the direct costs of treating CVHC and indirect costs, including those associated with a shortfall in the contribution to the gross national product due to temporary or permanent disability of this category of patients.
Conclusion. The analysis showed that interest in assessing the global burden of CVHC began to appear in recent years, when expensive directacting antivirals for the treatment appeared. This is explained by the emergence of a question about the cost of implementing a scenario in which by a certain year it will be possible to completely exclude the spread of the disease. The results of this work may be useful in conducting such studies, including the determining of their design and the use of modern mathematical modeling tools.

537-547 453

Background. Long-term use of chondroprotective agents – chondroitin sulfate (CS) and glucosamine sulfate (GS) in the treatment of osteoarthritis puts forward increased requirements for the safety of drugs, primarily in terms of effects on the liver and kidneys.
Objective: systematization of data on the effect of chondroprotectors on liver structure and functions.
Material and methods. Using the methods of the theory of topological text analysis, an intellectual analysis of 2319 publications on fundamental and clinical studies of the relationship of CS and GS with liver function was carried out. The search was performed by a key query “(chondroitine OR glucosamine) AND (liver OR hepatic OR hepatocy*)” in the PubMed/MEDLINE database.
Results. The systematic analysis indicated a pronounced hepatoprotective effect of CS and GS pharmaceutical substances with a high degree of purification from inorganic and organic impurities. By regulating inflammation processes, lymphocyte function, fat and carbohydrate metabolism in the liver, standardized forms of CS and GS have a beneficial effect on fat metabolism, reduce chronic inflammation in the liver, exhibit antitumor and pronounced hepatoprotective effects on various models of liver intoxication.
Conclusion. The results of this analysis allow us to assert the high safety of drugs based on pharmaceutical standardized forms of CS and GS in terms of liver function.

549-562 322

Background. Today, the development and widespread use of digital technologies in medicine is considered as one of the most promising mechanisms for optimizing costs and improving the efficiency of healthcare and the quality of life of the aging society.
Objective: to study the experience of using telemedicine technologies for providing medical care in the health systems of different countries, including the Russian Federation.
Material and methods. To obtain the necessary information, an overview of the most relevant studies published in Medscape, PubMed/ MEDLINE, ScienceDirect, Scopus, eLibrary, CyberLeninka databases, World Health Organization repository and open sources from Google and Yandex search, as well as relevant regulatory documents was carried out.
Results. The experience of using telemedicine technologies for medical care in healthcare systems of different countries, including Russia, presented in the article, demonstrates both the advantages of these technologies, and the limitations for their use in healthcare.
Conclusion. Despite all the undisputed advantages of telemedicine technologies, their development should not become an end in itself. The expediency of their use in each specific case of providing medical care and exclusively as another, additional tool to improve the quality and accessibility of medical care should be considered.

563-579 280

Background. The complex mechanisms of action of chondroitin sulfate (CS) and glucosamine sulfate (GS) at the molecular level make it possible to assert the applicability of the corresponding drugs far beyond chondroprotection. Inhibition of proinflammatory mechanisms (NF-κB, activation of toll-receptors, increased levels of cytokines, degranulation of mast cells, etc.) by CS and GS provide the prospects for their use to inhibit inflammation in the respiratory tracts, allergic processes and to enhance the effects of glucocorticoids.
Objective: to systemize data on the effects of chondroitin sulfate and glucosamine sulfate on pathophysiological processes in pulmonary pathology.
Material and methods. Using the methods of the theory of text topological analysis an intellectual analysis of 1273 publications on fundamental and clinical studies of the relationship of CS and GS with lung function was carried out. The search was performed by a key query “(glucosamine OR chondroitin) AND (lung OR lungs OR pulmonary OR pulmonology)” in the Pubmed/MEDLINE database. As a result, 59 informative biomedical terms were identified.
Results. The chemoproteomic study of CS and GS showed that their intake promoted an increase in the expression of 19 antitumor proteins and a decrease in the expression of 25 pro-inflammatory proteins involved in lung function. CS and GS can be used in the complex therapy of infectious diseases of the lungs, with fibrotic changes in the respiratory tracts and, as well, help to reduce the risk of neoplastic diseases of the lungs.
Conclusion. The results of this analysis allow us to assert the promising nature of the use of CS and GS in several neoplastic diseases of the lungs, as well as the high safety of drugs based on pharmaceutical standardized forms of CS and GS in terms of lung function.

581-592 558

Objective: to review domestic and foreign literature on the issue of machine learning methods applied in medical information systems (MIS), to analyze the accuracy and efficiency of the technologies under study, their advantages and disadvantages, the possibilities of implementation in clinical practice.

Material and methods. The literature search was performed in the PubMed/MEDLINE databases covering the period from 2000 to 2020 (using groups of keyphrases: "machine learning", "laboratory data", "clinical events", "prediction diseases"), CyberLeninka ("machine learning", "laboratory data", "clinical events", "prediction diseases" Russian keyphrases combinations) and Papers With Code ("clinical events", "prediction diseases", "electronic health record"). After reviewing the full text of 30 literature sources that met the selection criteria, the 19 most relevant articles were selected.

Results. An analysis of sources that describe the application of artificial intelligence techniques to obtain predictive analytics, taking into account information about patients, such as demographic, anamnestic, and laboratory data, the data of instrumental studies, information about existing and former diseases available in MIS, was performed. The existing ways of predicting adverse medical outcomes using machine learning methods were considered. Information about the significance of the used laboratory data for constructing high-precision predictive mathematical models is presented.

Conclusion. Implementation of machine learning algorithms in MIS seems to be a promising tool for effective prediction of adverse medical events for wide application in real clinical practice. It corresponds to the global trend in the development of personalized medicine based on the calculation of individual risk. There is an increase in the activity of research in the field of predicting noncommunicable diseases using artificial intelligence technologies.

593-631 271

The three-report review is aimed to describe the historical development of clinical trials, controlled trials (CT) and randomized controlled trials (RCT), and the inclusion of these approaches in health-related disciplines (Medicine and Epidemiology). Report 3 summarizes historical milestones (ideas and studies) for quasi-randomized CT (‘alternate allocation’; 88 milestones) and RCT (37 milestones). It was found that although the ideas of both designs are a thing of the past (from A. Lesassier Hamilton (1816) and J.B. Van Helmont (1648), respectively), the bulk of the tests were carried out in the 20th century, when both designs existed in parallel. Overall, the alternate allocation was used nearly three times longer than randomization.
Analysis of the sources showed that the first RCT in medicine was the work of D. Colebrook, 1925 (Great Britain), and the first close to the modern RCT, including randomization according to the table of random numbers, was J.A. Bell, 1941 (USA). Often referred to as the ‘new era in CT’ and ‘the origine of RCT’, a study of the effects of streptomycin on tuberculosis in 1946–1948, which was also designed by A.B. Hill is only 13th known RCT, only 9th RCT in medicine and only the 2nd with modern randomization. Other facts of insufficient reflection of the priorities and real history of CT/RCT in West and Russian publications were found, including dozens of Western textbooks on epidemiology and evidence-based medicine of recent decades. True priorities are often omitted, and the most frequent references to the history of CT (progressively) are the experience of the prophet Daniel, the experience of the surgeon J. Lind, and the study on the effect of streptomycin on tuberculosis in 1946–1948.
Based on a PubMed/MEDLINE search, a summary of alternate allocation CT, and RCT for the period 1960–1990 to 2020 is provided. In the first case, single publications were found, but the fact that design with alternation survives to this day is important. For RCT, since 1990s, an increase in the number of papers (up to tens of thousands per year) has been revealed. The data are given for the total number of RCTs performed by countries, continents and parts of the world for 2020. According to the calculated index of the ratio of the number of RCTs to the specific number of doctors (per 100,000 population) among 45 countries of Eurasia (from France to Tajikistan), Russia ranks 12th.
A three-report review based on the originals of nearly all publications from the late 19th century and including the necessary references and citations can serve as a reference guide to the historical development of CT and related topics.

ISSN 2070-4909 (Print)
ISSN 2070-4933 (Online)