In 2016 the WHO Assembly defined a global strategy to combat viral hepatitis viruses, which seeks to eliminate these infections by 2030. The most important goals of this programme, adopted by 194 countries, are to reduce the incidence of viral hepatitis by 90 % and mortality rates – by 65 % as compared to the levels observed in 2016. Therefore, there is an obvious need for development of medicines for the treatment of chronic hepatitis C. The aim of the present paper was to determine basic approaches to planning pre-authorisation clinical trials for the main groups of medicines for the treatment of chronic hepatitis C. The paper summarises the current trends in the treatment of chronic hepatitis C; it lists medicines with direct antiviral effect that are currently registered in the Russian Federation, as well as interferon-free and interferon-containing regimens for the treatment of this disease. The authors examined the current requirements in force in the Russian Federation, namely: the Federal Law No. 61-FZ «On circulation of medicines» dated April 12, 2010, the Guideline on Evaluation of Medicinal Products, the Clinical Recommendations for Diagnosis and Treatment of Adult Patients with Hepatitis C, as well as recommendations of the European Medicines Agency and the Food and Drug Administration in order to analyse the planning of programmes of pre-authorisation clinical trials of interferon alfa products and direct antivirals. 

In recent years, there has been an increasing interest in the development of combination medicines (fixed drug combinations) containing two or more active ingredients in a single dosage form. Therefore, there is an urgent need to develop an optimal programme of pre-authorisation clinical trials for combination medicines. The aim of the paper was to summarise modern science-based approaches to clinical development of combination medicines and identify possible ways of their practical implementation, taking into account the requirements of the current legislation. The author reviewed scientific publications devoted to creation of fixed drug combinations and analysed the regulatory documents defining regulatory requirements for pre-authorisation clinical studies of medicines in the Eurasian Economic Union, the Russian Federation, and other countries. Based on the results of the analysis the author described the general regulatory requirements for planning clinical studies of combination medicines for the purpose of their subsequent authorisation in the Russian Federation (via the national procedure) and the Eurasian Economic Union (via the centralized procedure). The pre-authorisation clinical development programme should be designed individually for each combination medicine. The selection of an optimal clinical trial strategy will make it possible to obtain sufficient information on the efficacy and safety of a combination medicine for its subsequent authorisation.

There are no specific requirements and recommendations in the Russian Federation for evaluation of bioequivalence of modified-release medicinal products. Until recently, modified-release products were regulated in a similar manner as immediate-release products, which is unacceptable considering the active ingredient release profile and its pharmacokinetics. The modified release characteristics require a more complex approach to the assessment of equivalence of generic medicines as compared with the reference product. The number of parameters to be assessed and the scope of testing depend on many factors (release mechanism, specific features of the dosage form, linearity of pharmacokinetics, potential for ingredient accumulation, dependence on food intake, dose-dumping effects, and the number of dosage strengths to be registered). The aim of this paper was to develop recommendations for the national procedure of modified-release products authorisation based on the analysis of international regulatory experience in this field. The paper reviews the current European Medicines Agency (EMA) guidelines on evaluation of bioequivalence of generic modified-release dosage forms for oral use that were taken as a basis for the development of Eurasian Economic Union regulations on bioequivalence assessment. The analysis of the above-mentioned documents made it possible to develop recommendations for the national procedure of modified-release products authorisation. In the case of modified-release products for oral use it is recommended to perform bioequivalence studies by comparing the test product with the reference product. The authors developed a procedural algorithm for bioequivalence studies of modified-release medicinal products.

Criteria for evaluation of clinical efficacy make it possible to assess the risk-benefit ratio of anticancer medicines that patients receive, in particular, for the treatment of solid malignant tumors. A medicine’s efficacy is assessed using special criteria called the endpoints of clinical efficacy, allowing most objective assessment of study results. It was demonstrated that nowadays clinical efficacy of anticancer drugs is assessed using «patient-centered» (overall survival and quality of life) and «tumor-centered» (response to therapy, progression-free survival, disease-free survival) endpoints. «Patient-centered» endpoints make it possible to evaluate the direct clinical benefit of chemotherapy in patients, while «tumor-centered» endpoints allow for evaluation of efficacy at earlier stages, without directly reflecting the clinical benefit. The analysis of the most suitable endpoints with the aim of making them interchangeable with the primary outcome measure – overall survival – is becoming more and more relevant in oncology. The choice of criteria of efficacy should be made taking into account the specific features of a particular oncological disease, study population and duration of therapy. The authors of the study analysed Russian and foreign literary sources containing information on criteria of efficacy of anticancer medicines and highlighted the advantages and disadvantages of these criteria. The study showed that clinical endpoints should be clinically significant, sensitive to therapy, easy to measure and interpret. It was demonstrated that comprehensive evaluation of outcome measures makes it possible to adequately assess the risk-benefit ratio of anticancer medicines.

The management of post-approval changes to registration dossiers for medicinal products is one of the most important factors for ensuring sustainable quality, safety and efficacy of medicines. Competent authorities that use the module format of the registration dossier, i.e. the regulatory authorities of the European Union, USA and other members of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and the Eurasian Economic Union (EEU), issue guidelines on changes to registration dossiers for pharmaceuticals and biologicals (immunological products). Vaccines (finished dosage forms) and vaccine antigens (active ingredients) are a specific group of immunobiological products which have great prophylactic importance for healthcare, and which are associated with challenging development and specific methods of manufacturing and quality control. The procedure of introducing post-approval variations to dossiers for immunobiological medicinal products is poorly reflected in the current Russian and EEU regulations. The World Health Organization (WHO) established a procedure described in the «Guidelines on procedures and data requirements for changes to approved vaccines». The purpose of the present study was to compare current Russian and international legislation in terms of regulatory requirements for post-approval сhanges to dossiers for immunobiological products. The Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health of the Russian Federation is drafting Guideline on introducing post-approval changes into dossiers for immunobiological medicines. The draft includes a detailed review of various categories of changes based on their importance, and a list of conditions and required documents for specific groups of medicines. This article summarises scientific and methodological approaches to evaluation of changes introduced in registration dossiers for vaccines in order to further improve the regulatory framework of the Russian Federation and the EEU.

The article summarises the main results of a study investigating integrated development and implementation of an information analytical database of reference standards in the Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health of Russia (FSBI «SCEEMP»). The subject of the research is an information analytical database of reference standards designed to assess the quality, efficacy and safety of medicines. The aim of the study was to create the concept of an information analytical database of reference standards based on object-oriented approaches. The database was created in response to the need for improving the efficiency of certain types of activities of the FSBI «SCEEMP» which has already automated some of its processes. The paper discusses the key prerequisites for the creation of an integrated specialised information technology product as a way to improve overall performance. A general procedure for the development of an information and analytical database is presented, taking into account the tasks set and the established requirements for the functionality of the information and analytical system. The paper describes the implemented solutions, as well as strategies for their improvement. The operation algorithms of the information-analytical database of reference materials allow for its further modernisation, as well as greater automation of actions with documents and data, incorporation of new standardised reference books, ready-made templates, as well as modification  in case any changes are made to business processes, legislation or technical and technological aspects of using reference standards.

The work is a continuation of the research on the use of NMR spectroscopy in the quality control of natural peptide hormone-based active substances and their synthetic analogues. The aim of the paper was to develop identification test methods for triptorelin acetate and goserelin acetate substances using NMR spectroscopy that does not require reference standards ‒ with the aim of using the newly developed test methods in pharmacopoeial analysis. Materials and methods: the procedure was developed using two-dimensional NMR spectroscopy (¹H-¹H gCOSY, ¹H-¹³C gHSQC, ¹H-¹³C gHMBC). Results: thestudy made it possible to assign ¹H and ¹³C NMR signals to a specific molecular fragment, and to determine the amino acid composition of each oligopeptide. Conclusions: the authors drew up a table showing structural assignment of NMR signals, which makes it possible to use the NMR method for identification testing of triptorelin acetate and goserelin acetate substances without the use of pharmacopoeial reference standards. The study helped to determine the optimal temperature conditions for recording ¹³C NMR spectra (27 °С and 50 °С for triptorelin acetate and goserelin acetate, respectively). It was demonstrated that ¹³C NMR spectroscopy could be used for identification testing in pharmacopoeial analysis.