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INTRODUCTION. The stability assessment of biological medicinal products (BMPs) requires special approaches and regulatory requirements. Therefore, BMPs require relevant national guidelines, which are an important prerequisite for the assurance of the safe and effective use of BMPs.AIM. This study aimed to analyse national and international requirements for the stability assessment of BMPs in order to use the results to inform future development of a unified regulatory approach to estimating and confirming shelf-life periods for BMPs.DISCUSSION. Most biotechnological medicinal products (BTMPs) are proteins and are highly sensitive to environmental factors by nature. Therefore, the shelf life of a BTMP is established on the basis of real-time stability studies. Stability testing under accelerated and stress conditions is conducted to support shelf-life claims and to characterise the mechanism of protein structure degradation. The results of accelerated and stress studies can be used to select the most sensitive stability-indicating parameters and testing methods. National and international regulatory authorities have developed specialised guidelines for stability studies of BMPs of various origins, and the stability assessment approaches in the regulatory system of the Eurasian Economic Union (EAEU) are harmonised with international standards. Special considerations associated with the stability of vaccines imply that stability studies of vaccines should not only establish shelf life but also investigate stability after reconstitution and after short-term temperature excursions from the recommended cold-chain conditions.CONCLUSIONS. Special stability testing considerations for various groups of BMPs (including BTMPs and immunobiologicals) indicate the need to develop and improve the system of requirements for BMP stability assessment. This will facilitate the optimisation of the life cycle of BMPs in the Russian Federation and the other EAEU member states.

Scientific relevance. In recent years, the development of various vaccines based on novel platforms has underscored the significance of updating regulatory requirements for vaccines. Consequently, clinical trials of viral vaccines need harmonised approaches within national guidelines and the Eurasian Economic Union (EAEU) regulatory framework.Aim. This study aimed to analyse national and international requirements for clinical trials of the efficacy and safety of preventive viral vaccines.Discussion. This article presents an analysis of the guidelines issued by the WHO and leading regulatory authorities on different aspects of clinical trials of viral vaccines. These guidelines place particular emphasis on the immunogenicity of vaccines. The lack of well-established immune correlates of protection for most infections presents a significant problem for assessing the effectiveness of vaccines. Immunobridging studies may be conducted to expand vaccine indications to different populations (such as a new age group). The size of the prelicensure safety database should include data on at least 3,000 vaccinated study participants. For some vaccines, safety studies must assess the risk of disease onset or enhancement due to vaccination.Conclusions. The clinical trial requirements for viral vaccines have been substantially aligned by the WHO and major international regulatory authorities, thereby facilitating the development of harmonised national or EAEU guidelines.

Vaccines are subject to specific regulatory requirements for the evaluation of their quality, safety, and efficacy. In 2005, the World Health Organisation (WHO), as the main international organisation coordinating measures to combat infectious disease outbreaks, began developing documents on the evaluation of vaccine quality, safety, and efficacy. The world’s leading regulatory authorities (FDA, EMA, etc.) have also issued recommendations for conducting non-clinical studies of vaccines.The aim of this study was a critical review of the regulatory requirements established by foreign national and international regulatory authorities for non-clinical evaluation of the safety and efficacy of vaccines.According to the study results, since the 2000s, the WHO and the world’s leading regulatory authorities have produced more than 40 regulatory documents describing certain aspects of non-clinical studies of the safety and efficacy of vaccines. These documents can be divided into two groups: the first group addresses non-clinical studies of vaccines in general, and the second one dwells upon the evaluation of the quality, safety, and efficacy of specific types of vaccines. For the Russian guidelines on non-clinical evaluation of the quality, safety, and efficacy of immunobiologicals, the latest revision dates back to 2013 and does not provide any information on new medicinal products. Currently, work is underway to prepare the regulatory framework for medicines, including vaccines, in the Member States of the Eurasian Economic Union (EAEU). This review of regulatory documents on non-clinical safety and efficacy studies of vaccines may be useful in drafting harmonised guidelines for the relevant groups of vaccines in the EAEU. It may also be of use to developers, manufacturers, and researchers involved in the creation and non-clinical study of vaccines.

There are a lot of diseases known today, which are caused by genetic abnormalities. Advances in genetics and biotechnology brought about gene editing technologies that can produce almost any gene, which ultimately led to the emergence of a new class of medicines - gene therapy products (GTPs). The aim of the study was to analyse international experience in development and authorisation of GTPs. The review highlights the challenges in GTP development, related to the search for an optimal approach to therapeutic gene delivery to the target cells. Viral vectors were shown to be a promising gene delivery system, with adenovirus (AV) and adeno-associated virus (AAV) based products demonstrating the highest efficacy and safety. The paper reviews current approaches to gene editing that allow modification of AVs and AAVs to improve GTP efficacy and safety. These modifications are carried out with the aim of, e.g., including a large therapeutic gene into a viral vector, decreasing viral protein expression levels, and decreasing viral vector immunogenicity. The review summarises GTP authorisation procedures in the USA and the European Union, including data on FDA and EMA subcommittees and departments entrusted with advisory functions. The paper mentions that there is one Russian-produced GTP authorised in the Russian Federation, and some other GTPs are in the pipeline. Therefore, the Russian regulatory framework and the Eurasian regulations and recommendations should be updated in order to accommodate for GTP development and authorisation.

Continuous replacement therapy with clotting factor products can lead to serious complications in haemophilia A patients. One of potential reasons of such complications is an undesirable immune response to a blood clotting factor VIII (FVIII) product, which undermines the treatment effectiveness. The aim of the study was to systematise and summarise data on undesirable immunogenicity of plasma-derived and recombinant FVIII products, formation of immunological tolerance, and modern approaches to the development of clinical trial programmes for such products. The analysis was based on scientific literature, as well as Russian and international guidelines, including the updated document of the European Medicines Agency. The paper presents clinical trial data on pharmacokinetics, efficacy, and safety of FVIII products, including data on manifestations of unwanted immunogenicity. It highlights molecular mechanisms of interaction between inhibitors and FVIII, and analyses the main factors (genetic characteristics, immune status of patients, dosage regimen, etc.) affecting the frequency and intensity of the immune response to the product. The authors summarised approaches to the clinical trial design, including selection of patients and studied parameters. They substantiate the need for post-authorisation studies to collect additional clinical data on both efficacy and safety of the routine use of the product, including additional assessment of immunogenicity and other adverse reactions. It is concluded that the successful use of high-quality FVIII products ensures by harmonisation of requirements of Russian and international regulatory documents.

According to the World Federation of Hemophilia (WFH), there are currently about 400 thousand patients with hemophilia in the world. Severe clinical manifestations of the disease associated with a genetically determined deficiency of blood clotting factor activity require continuous replacement therapy with blood clotting medicines. Long-term use of protein-based medicines often leads to the formation of specific antibodies, which causes a decrease in or loss of efficacy of the medicine or results in severe adverse reactions, including anaphylaxis. Therefore, it is important to search for new optimal approaches to hemophilia treatment, which requires the development of new blood clotting factor products, improvement of the production technology for already authorised products, as well as the use of non-factor products. The aim of the study was to present the results of the analysis of key issues related to the development and characteristics of plasma-derived and recombinant factor VIII products, new approaches to hemophilia A treatment, including the use of non-factor products. The review summarises current data on the etiology, clinical manifestations, and complications of hemophilia A treatment. It provides information on the blood clotting factor products (plasma-derived and recombinant) used as replacement therapy. It also provides information on advanced research projects for the development of new biotechnology-derived products which have good prospects of successful clinical use.

One of the major public health challenges today is development of new vaccines and technologies to optimize the vaccination process. There is a growing scientific interest in vaccine adjuvants that enhance vaccine immunogenicity. At present, numerous studies are underway to develop COVID-19 vaccines, including inactivated and subunit vaccines which contain adjuvants for efficient induction of immune response and solid immunity. The aim of the study was to systematise literature related to the analysis of the structure, mechanisms of action and stimulating properties of vaccine adjuvants (synthetic oligodeoxynucleotides, virosomes, polyoxidonium, sovidone), as well as to summarise data on the effects of adjuvants used in SARS-CoV, MERS-CoV, and SARS-CoV-2 vaccine development studies. The paper analyses the prospects for enhancing the stimulating effect of the adjuvants when used in combination with compounds having a different mechanism of action. It also analyses the results of studies of adjuvanted vaccines against SARS-CoV and MERS-CoV, which may be useful when selecting adjuvants with optimal efficacy and safety profiles to be used in SARS-CoV-2 vaccines under development. It was concluded that understanding of the mechanisms of action of adjuvants that mediate their stimulating effect on the body’s immune system will contribute to safe and effective use of adjuvants to enhance the immunogenicity of both authorised and new vaccines.

One of priority issues of the present-day healthcare system is development of new vaccines and improvement of existing ones due to decreasing immunocompetence of the population, emergence of new infections and reemergence of old ones which were previously thought to be under control. Adjuvants have proven to be integral and important components of modern vaccines, as they enhance immune response to the vaccine antigen. However, despite a lot of effort put into their development, only a small number of adjuvants are currently used in clinical practice. The aim of the study was to systematise literature data on the adjuvants’ mechanisms of action, their specific structure, composition, and stimulation effects that mediate their immunoadjuvant properties. The paper summarises data on adjuvants used as components in licensed vaccines, describes their characteristics, analyses molecular mechanisms of their action in order to establish correlation between their structure and activity, which is important for the development of more efficacious and safe adjuvants. The paper cites advanced developments aimed at enhancing stimulation effects of existing adjuvants. It concludes by stating that the key research area aimed at improving vaccination efficacy is the study of mechanisms that contribute to the development of effective protection against infectious agents, as well as analysis of how to use adjuvants to stimulate the body’s defensive mechanisms, primarily by impacting the innate immunity.

The progress of the COVID-19 pandemic initiated research to develop vaccines against this novel coronavirus infection. The WHO and national regulatory authorities in many countries have elaborated guidelines to speed up the development and authorisation of COVID-19 vaccines. The aim of the study was to analyse international and Russian regulatory recommendations for the development and fast-track approval of COVID-19 vaccines in the context of the pandemic, as well as to summarise the preliminary published results of the first stages of preclinical and clinical studies. The paper analyses approaches to fast-track approval of medicines in the face of the pandemic in Russia, the European Union, and the United States. It summarises regulatory requirements for the quality of COVID-19 vaccines, as well as for preclinical, and clinical studies. It describes the first results of COVID-19 vaccine development. The analysed regulatory documents allow for accelerated authorisation due to reduction of time spent on evaluation of vaccine quality, safety, and efficacy. Another option is the so-called conditional marketing authorisation when a vaccine is registered based on incomplete preclinical and clinical data provided that all the studies will be completed after the vaccine authorisation. The paper summarises the results of clinical trials of COVID-19 vaccines. The few published preliminary results of the first phases of COVID-19 vaccine clinical trials demonstrate the vaccines’ good tolerability, safety, and immunogenicity. Evaluation of adenovirusbased vaccines showed that almost half of the volunteers had had high antibody titers to adenovirus before the study, which resulted in milder adverse reactions and low immunogenicity. In addition, the immune response was weaker in the older group of subjects (45–60 years) as compared to the subjects younger than 45 years. The results of the analysis of regulatory requirements for the development and marketing authorisation of COVID-19 vaccines in the context of the pandemic, as well as of national and international regulatory approaches to vaccine development and authorisation can be used as a basis for the development of Russian requirements for COVID-19 vaccines in the context of the pandemic.

The review article presents the materials of recent years dedicated to the analysis of modern data about the possible aspects of the use of deoxyribonucleic acid (DNA) and oligodesoxinucleotides (natural and synthetic) from pro - and eukaryotes for the prevention and treatment of infectious diseases.The authors focus on bacterial DNA with a high content of CpG motifs, as well as on unmethylated CpG oligonucleotides (CpG-ODN), which stimulate the system of innate and adaptive immunity. Due to the absence of pronounced toxicity and good tolerance of the macroorganism, these compounds are of great interest for medical use, in particular as adjuvants. At the same time, the authors note the need to develop effective CpG-ODN delivery systems in tissues and target cells.With respect to CpG-motives of eukaryotic DNA, the possibility of their use as a basis for effective adjuvants, immunomodulators, antiviral and antibacterial compounds is considered.

Hemophilia is an orphan disease associated with deficiency or complete lack of certain blood coagulation factors due to mutation of genes encoding their synthesis. Patients with hemophilia need continuous replacement therapy with coagulation factor products which are produced by recombinant DNA technology or derived from donated blood plasma. The development of new products or improvement of the production process of already authorised medicinal products involve clinical trials that have to include both previously treated and untreated patients of different age groups. The aim of the paper was to perform an analytical review of general hemophilia issues and major requirements for clinical trials of coagulation factor IX products based on the updated documents of the European Medicines Agency. The paper summarises the basic principles of conducting clinical trials of coagulation factor IX products that are submitted for marketing authorisation as “new” products, based on recommendations of Russian and international regulatory documents, including the updated guideline of the European Medicines Agency. It sums up product safety issues associated with undesirable immunogenicity resulting in formation of inhibitors that provoke allergic reactions or reduce the effectiveness of therapy. The harmonisation of the requirements for clinical trials during preparation and updating of documents by Russian manufacturers should be based on the analysis of the experience with hemophilia products and latest scientific achievements in the disease treatment. In that case it will facilitate the introduction of innovative efficacious hemophilia products into clinical practice.

The review is devoted to specific aspects of the development of post-vaccination immunity following immunisation with different types of antiviral vaccines, as well as to ways of increasing immunogenicity of vaccines and effectiveness of preventive vaccination. Vaccines containing highly purified and recombinant antigens obtained using modern technologies have lower reactogenicity and a higher safety profile, but are less immunogenic compared to live vaccines. Effective vaccines have not been developed for many viral infections yet. Therefore, it is critical to search for ways to enhance immunogenic properties of vaccines in order to increase the efficiency of vaccination, and to develop new vaccine formulations that provide reliable protection of the body against infection. The aim of the paper was to analyse specific aspects of immune response development following immunisation with antiviral vaccines, and approaches to increasing their immunogenicity using adjuvants. It reviews different types of antiviral vaccines, as well as specific aspects of immune response development depending on the nature of a specific antigen. The paper substantiates the use of adjuvants to enhance and regulate the induced immune response. It analyses mechanisms that determine the stimulating effect of adjuvants and summarises data on the adjuvants used in the licensed vaccines for human use. The authors highlight the need for further research to increase the efficiency of vaccination and suggest that one of potential solutions is the use of adjuvants based on recombinant human cytokines.

European competent authorities began to elaborate scientific principles of development of non-innovator biotherapeutic (biosimilar) products in the early noughties, and in 2009 these principles were approved at the WHO International Conference in Seoul gathering participants from countries with a well-developed pharmaceutical industry. The USA adopted the law on biosimilar products in 2012, it was based on the documents and recommendations prepared by the EMA and approved by the WHO. In 2015, the FDA published the new revised versions of the guidelines dealing with biosimilar products. The US regulatory requirements for development and authorisation of biosimilar products are based on a step-by-step comparative assessment of biosimilar and innovator products in terms of their quality, efficacy, and safety in accordance with the WHO/EMA recommendations. At the same time the US regulatory requirements differ from those of other national authorities, including EMA (WHO), when it comes to the design of comparative quality studies (studies of products’ physicochemical and biological properties), the assignment of International Non-Proprietary Names and the interchangeability of biosimilar products.

The paper presents the data on safety and efficacy assessment of adjuvants and vaccines with adjuvants at the stages of development and preclinical studies based on international recommendations. The presence of an adjuvant in vaccine content ensures higher expressing and prolonged specific immunity. The origin and nature of adjuvants currently used for various vaccines are different. Adjuvants can be classified by origin, mechanism of action, physical and chemical properties. The finished vaccine may contain one or more adjuvants which can be intended for one antigen or a number of antigens in vaccine content. Antigen-adjuvant combination is a key part in the production of a vaccine with an adjuvant. Due to the diversity of adjuvant nature and their physical and chemical properties and mechanisms of action, as well as to antigens in adjuvant vaccines content, it is rather complicated to plan and to conduct preclinical studies. The present article describes various aspects of preclinical studies of adjuvants and vaccines with adjuvants based on the analysis of current guidelines and requirements.

The review looks into various aspects of assessing specific activity of biotechnological products, which is one of their key quality parameters. Approaches to the analysis of this parameter and the choice of test procedures are governed by the nature and characteristics of a medicinal product. Test procedures should be adequate and have sufficient sensitivity and specificity. Specific activity of the products in question can be assessed by biological methods both in vivo using laboratory animals, which demonstrate the most adequate response to the tested product, and in vitro using sensitive cell lines. Assessment of specific biological activity helps to characterize the product’s pharmacological action and systematically examine the mechanisms of therapeutic effects in clinical practice. Therefore, specific activity of biotechnological products should be assessed using methods appropriate for the proposed mechanism of action. Many biotechnological products, such as cytokine system products, mAbs, fusion proteins and some others call for individual methods for assessment of their specific activity. Biotechnological products are successfully used in the treatment of autoimmune, infectious, oncological, and allergic diseases.

The article describes general principles of evidence-based quality assessment research of a recombinant granulocyte colony stimulating factor preparation (G-CSF) under development as well as a confirmation of its similarity to reference preparation (authorized original preparation). Since the quality of biotech preparations is determined by the manufacturing process, when developing a biosimilar one should focus on the manufacturing process details, starting from the selection of the expression system, the composition of excipients, on to the methods of isolation and purification of recombinant protein. Recombinant protein should be characterized in more details, than the quality parameters of the original preparation, included in the specification of the substance or the preparation. Comparative studies include characterization of the active substance and the assessment of the quality of the finished product. The reference preparation in the development of a biosimilar G-CSF

One of the most complicated issues of modern medicine is diagnosis, treatment and prevention of rare diseases. In the structure of rare diseases the vast majority accounts for genetically determined disorders. The introduction of genetic testing methods helped to identify a lot of hereditary diseases, that currently reach the number of 8,000 cases and according to estimations the frequency of their detection is about to increase. Medicinal products for diagnosis or treatment of rare diseases form the group of orphan drugs. Biologicals are the most effective medicinal products in the whole group, due to their ability to bind specifically with the «target receptor», which allows to use them as targeted drugs. Another advantage of biologicals, compared with preparations of chemical origin, is their low toxicity. Orphan drug provision is the most severe issue because the treatment of severe forms of rare diseases may require the prescription of an expensive drug. Manufacturing of orphan drugs may be unprofitable for the reason of the low prevalence of rare diseases. Therefore, the availability of orphan drugs for patients depends on the amount of state participation in manufacture stimulation. In various countries regulatory requirements for the recognition of a disease as a rare disease, and marketing authorization procedures for orphan drugs are developed with due regard to the social and economic characteristics of the country. The article presents the analysis of the regulatory requirements for various countries for the detection of rare diseases, and a common approach to marketing authorization procedure for the drugs used in treatment of rare diseases, exemplified by biological orphan preparations.

The use of the reduced scheme in preclinical and clinical studies of «biosimilars» requires special attention to the safety issues. During the process of the marketing authorization of biosimilars in 2013-2015 the countries with advanced regulatory and pharmacovigilance systems (USA, Canada and EU countries), the most contentious debates were provoked by the issues of extrapolation of the results of the research of a biosimilar infliximab (TNFα-specific monoclonal antibodies). EMA made the decision that the results of the efficacy and safety studies of infliximab, obtained in adult patients with rheumatoid disease, can be extrapolated to the indications for the treatment of inflammatory bowel disease (Crohn’s disease and ulcerative colitis in adults and in children). Several medical associations such as the Association of Gastroenterologists and the Association of Pediatricians believe that this extrapolation is not justified. Health Canada also made a conclusion that the extrapolation is not justified and did not approve the use of the mentioned preparation for the treatment of Crohn’s disease and ulcerative colitis. There is still an ongoing hot discussion on the issue of interchangeability of an original medicine and a biosimilar. Given that the safety of a biosimilar has been studied before obtaining marketing authorization not to the fullest extent, usually safety studies continue after obtaining marketing authorization for a few more years. If there is an interchange of medicines, then it is not possible to objectively evaluate the safety of a biosimilar. In the countries with poor regulatory and pharmacovigilance system not only «biosimilars» are in drug circulation system, but also other medicines registered under the reduced studies scheme, but not in full compliance with the principles of «biosimilarity». The quality of these medicines does not always meet the standards, as evidenced by numerous studies. WHO is concerned about the quality of the mentioned medicines and suggests to call them «non-innovators» and establish a separate group, and claimed that the sponsors were invited for a certain period of time to provide the evidence of the high quality of these medicines.

The review provides with the information, related to the development, research and registration of new biological preparations, including the issues of terminology and classification. It also highlights the issues of and prospects for genetically engineered drugs, specific aspects of comparative studies to prove the similarity of a biosimilar and the original (reference) medicine, clinical use and interchangeability of preparations, prospects for the development of biotechnological medicines, expert evaluation of the quality of biological/ biotechnological medicines, modern methods of immunotherapy of allergic diseases by recombinant medicines, as well as the issues of cell technology and tissue engineering. The review also describes the topics discussed at the 14th International Conference «High Medical Technologies of 21st Century» (October 24-31, 2015, Spain), related to fundamental and applied research, development and introduction of new technologies and modern medicines into clinical practice.

The article provides the information on issues related to the clinical use of preparations of monoclonal antibodies (MAb), and the prospects for developing preparations based on modified MAbs. MAb preparations based on recombinant proteins show the consistency of physical and chemical properties as well as high specificity. New class of preparations based on MAbs show great potential of targeted therapeutic influence on important pathogenetic mechanisms of disease development. It has proved to be successful against severe chronic diseases such as autoimmune cancer, infectious and allergic diseases, as well as in transplantation for the treatment and prevention of transplant rejection. The development and manufacture of MAb preparations based on a whole immunoglobulin molecule, as well as preparations of modified antibodies with a specific set of functions associated with individual structural elements of the molecule is now possible due to genetic engineering and transgenic animals technologies. Preparations based on modified MAb can exist in

Biological preparations differ substantially from low molecular weight chemicals in molecular weight, multidimensional structure of an active substance, presence of post-translational modifications, composition of impurities and excipients, drug manufacturing process, etc. These specific features of biological preparations also influence their pharmacokinetic properties. The assessment of pharmacokinetic properties is essential not only for the confirmation of the efficacy of a biological preparation, but it is also key aspect of demonstrating the similarity/analogy of a biosimilar preparation under development and the reference (original) preparation. High molecular weight biological preparations when administered subcutaneously and intramusculary initially migrate from the injection site into lymphatic vessels and then to blood. Pharmacokinetic properties of drugs with Fc region of immunoglobulin, are affected by their ability to interact with Fcy and FcRn receptors. Almost all biological preparations possess immunogenicity, the appearance of antibodies to a drug causes changes not only in pharmacodynamic but also in pharmacokinetic properties of biological products. The assessment of pharmacokinetic properties is a complicated and time-consuming process, for example, the study of drug distribution may in some cases require the use of a radioactive label.

Adverse drug reactions (ADR) are injuries caused by taking a medication. For the purpose of an objective analysis of the reasons and mechanisms of ADR, with a view to developing the methods for their relief and prevention, one should use standard criteria for the characterization of ADR. Typically, the description of ADR includes information about the damaged organ or tissue and the frequency of ADR occurrence. To characterize ADRs caused by low molecular weight chemicals proposed, an A/B classification and its modifications have been proposed, based on the possible mechanisms of ADR. Biological preparations differ from chemicals by a number of characteristics, including the mechanism of action. Considering the nature of biological/biotechnological preparations, several types of ADR classifications, related to the mentioned drug group, have been suggested. The most popular classification for ADR related to biological preparations have been suggested by W. J. Pichler. It is based on the involvement of immunological mechanisms in ADR occurrence. This classification divides ADR related to biologicals into 5 types: type α (reactions caused by high level of cytokines), type β (hypersensitivity reaction), type γ (reactions caused by the imbalance of immune factors), type δ (cross-reactivity reactions) and type ε (reactions caused by non-immunological mechanisms). The mentioned classification method has certain disadvantages: it does not cover all biological preparations, but only drugs, containing cytokines, hormones and monoclonal antibodies preparations; and it does not consider ADR occurring without immune mechanisms (such as increased blood pressure when administering preparations of recombinant erythropoietins).

The review deals with the issues related to the special aspects of the development of the first available similar biopharmaceuticals/biological analogues («biosimilars») based on monoclonal antibodies. In June 2013 the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) approved for licensing Remsima and Inflectra which are biosimilars of the brand-name product Remicade® (infliximab). The review describes the general principles of the development of the mentioned biosimilars. It highlights the features of the quality assessment studies, including characterization of the physical and chemical properties, specific biological activity, as well as comparative preclinical and clinical trials confirming the similarity of the candidate and the brand-name (reference) product. The review provides with the analysis of the results of comparative studies to assess the clinical relevance of the differences detected at the stage of quality assessment. The data substantiating the possibility of extrapolating the results obtained in clinical trials, against the approved standards for the brand-name product is provided.

In 2009-2010 there was an influenza pandemic that occurred despite all preventive measures. Analysis of this pandemic revealed some gaps in the regulatory requirements applied both to the development of new influenza vaccines and to the change/update of the seasonal influenza vaccine strains. Taking into account the lessons learned from this pandemic the European Medicines Agency revised the existing guidelines in 2014-2016 and proposed new recommendations on quality evaluation and conduct of non-clinical and clinical trials in the development of influenza vaccines. The revised requirements encompass not only quality evaluation issues, but also changes/update of strain composition of seasonal, pre-pandemic and pandemic influenza vaccines. The experience acquired by the Agency can help update the Russian regulatory framework in order to improve efficacy and safety of influenza vaccines.