Search

US FDA requirements published in the new 2018 guidance for bioanalytical method validation and the necessity to confirm their reliability for determining analyte concentrations are reviewed. The history of regulations for bioanalytical method validation is briefly described. The key changes and additions to the FDA guidance for bioanalytical method validation that include unified requirements for chromatographic and ligand-binding method validation, instructions for biomarker validation, a separate section focused on new technologies (e.g., dry blood-spot method), and introduction of the fit-for-purpose concept are discussed. FDA and EAEU requirements for validation of chromatographic assay parameters are compared. In general, the requirements of the new FDA guidance and the EAEU agree despite several differences in the number of parameters and their acceptance criteria.

Generic drugs are widely discussed in the scientific literature. Their key advantage is high availability in the medical practice due to the possibility of a significant reduction in developer costs. In most cases the efficacy and safety of generic oral drugs are confirmed based on the acceptable results of pharmacokinetic evaluation of their bioequivalence with the reference drug. However, generic drugs are not directly compared with one another, and this calls into question the validity of the conclusion about the interchangeability of the generic drugs.The aim of this study was to evaluate the results of indirect comparison of generic drugs by the ratios of their AUC0-t and Сmax based on the information obtained in bioequivalence studies involving the reference drug.Materials and methods: the authors performed an indirect comparison of the results of bioequivalence studies of generic drugs containing one active pharmaceutical ingredient. The analysis was based on bioequivalence study reports over the last 7 years dealing with risk/benefit assessment of imatinib and tacrolimus products.Results: the results of indirect assessment of 90 % confidence intervals of the ratios of imatinib products’ geometric means show that in 46.7 % of cases the intervals fall outside the generally accepted limits (80–125 %) for at least one of the estimated parameters. As for tacrolimus products, the intervals did not go beyond the generally accepted limits (80–125 %) for the AUC0-t ratio, but a discrepancy was found in 10 % of cases for the Cmax ratio. However, when narrower limits of 90–111 % were used to assess the AUC0-t ratio, 90 % of the compared pairs did not meet the recommended standards. Conclusions: thus, conclusions on the acceptable degree of bioequivalence of two generic drugs to the reference product cannot constitute a scientifically sufficient reason for regarding these generic drugs as clinically equivalent.

The article presents a solution to the problem of calculating the parameters of a mathematical model of an electric hybrid stepper motor based on an analysis of the picture of its magnetostatic field. The main disadvantage of such an engine described. Is the mid-frequency resonance, which occurs due to the coincidence of the natural frequency of the rotor with the frequency of the supply voltage pulses. The necessity of taking this factor into account when designing a discrete electric drive system based on the executive motor of this type by calculating the values of resonant frequencies and using them in developing the drive control algorithm is shown. The task of developing a mathematical model of the engine is formulated, which allows to analyze the influence of its design parameters on the spectrum of resonant frequencies. The method of calculating the parameters of a given mathematical model is formed. The variants of the mathematical description of this electric machine are considered and the selection of its known mathematical model is made based on the equivalent electric circuit. The numerical calculation of the spatial pattern of the magnetostatic field of the electric motor is performed. Based on the analysis of the calculation results, a system of assumptions has been formed to develop an equivalent magnetic circuit of an electrical machine. An equivalent magnetic circuit and the corresponding system of equations has been developed. Formed a system of equations of a mathematical model based on the equivalent circuits of the electric and magnetic circuits.On the basis of the obtained system of equations, a simulation model of a discrete electric drive was developed in the Simulink software package. Using the obtained simulation model, the calculation of transients on the angle of rotation of the rotor and the electromagnetic moment is carried out and the influence of one of the design parameters on the natural frequency of the rotor is analyzed. Based on the simulation results, it is shown that with an increase in the air gap height of a hybrid stepper motor, the resulting electromagnetic moment decreases, and the natural oscillation frequency of the rotor decreases, and the frequency at which medium-frequency resonance occurs also decreases. This mathematical model can be used at the stage of the correct calculation of the selected engine, since allows you to analyze the effect of a specific design parameter of the machine — in particular the size of the air gap on the natural frequency of the rotor, and, consequently, on the spectrum of the resonant frequencies of a discrete electric drive.

The introduction of the «therapeutic equivalence» concept into the Russian legislation is critical for evaluation of medicines interchangeability and for recognising them as generics. It is stipulated by the legislation that therapeutic equivalence has to be evaluated using a special instrument — «therapeutic equivalence study». The aim of this work was to analyse the validity of considering a therapeutic equivalence study as the only study that allows for confirmation of therapeutic equivalence of medicines. The term «therapeutic equivalence» has been adopted by the leading world regulators, but there is no clear concept of what is a therapeutic equivalence clinical study. The key distinctive features of the foreign approach, as compared to the Russian one, are comparison of medicines with one active pharmaceutical ingredient, and additional conditions for the establishment of therapeutic equivalence. The clinical trial methodology, which is based on the use of statistical analysis methods, also imposes constraints on evaluation of «similarity» of properties, efficacy and safety of medicines in a single study. Hence, there are several reasons why the results of comparative clinical trials can not be used as a sole basis for the establishment of therapeutic equivalence. These results have to be substantiated by confirmation of comparable composition and pharmacokinetic parameters of medicines in order for them to be considered therapeutically equivalent. This does not contradict the existing regulatory framework and is consistent with the current scientific methodology for conducting clinical trials.

The need to strengthen the post-approval regulation of biological products stems from their increasing role in the treatment of serious human diseases. Until recently, there were open questions on the classification of changes and supporting data necessary to confirm the comparability of a biological medicinal product before and after any changes, as well as on the procedures and deadlines for the submission and approval of variations. In October 2017 the WHO Expert Committee on Biological Standardisation developed and published the «Guidelines on procedures and data requirements for changes to approved biotherapeutic products». The WHO recommendations are primarily aimed at resolving the complexities and current problems in the global life cycle management of biotherapeutic products. Guidelines suggest approaches that ensure continued quality, efficacy, and safety of this group of products, as well as continuity in supply and access. The purpose of this paper was to analyse the WHO recommendations on post-approval changes to biotherapeutic products in order to develop harmonised approaches to the assessment of post-approval changes to biological medicinal products in the Russian Federation. The categories of quality changes, supporting data, conditions to be fulfilled, procedures and deadlines set forth in this paper can serve as a basis for further improvement of the national regulatory and methodological framework.

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.

Single-crystal n-Si(100) wafers are implanted with 64Zn+ ions with an energy of 50 keV and dose of 5 × 1016 cm–2. Then the samples are irradiated with 132Xe26+ ions with an energy of 167 MeV in the range of fluences from 1 × 1012 to 5 × 1014 cm–2. The surface and cross section of the samples are visualized by scanning electron microscopy and transmission electron microscopy. The distribution of implanted Zn atoms is studied by time-of-flight secondary-ion mass spectrometry. After irradiation with Xe, surface pores and clusters consisting of a Zn–ZnO mixture are observed at the sample surface. In the amorphized subsurface Si layer, zinc and zinc-oxide phases are detected. After irradiation with Xe with a fluence of 5 × 1014 cm–2, no zinc or zinc-oxide clusters are detected in the samples by the methods used in the study.

The antiproton experiment PANDA at FAIR is designed to bring hadron physics to a new level in terms of scope, precision and accuracy. In this work, its unique capability for studies of hyperons is outlined. We discuss ground-state hyperons as diagnostic tools to study non-perturbative aspects of the strong interaction, and fundamental symmetries. New simulation studies have been carried out for two benchmark hyperon-antihyperon production channels: $\bar{p}p \to \bar{\Lambda}\Lambda$ and $\bar{p}p \to \bar{\Xi}^+\Xi^-$. The results, presented in detail in this paper, show that hyperon-antihyperon pairs from these reactions can be exclusively reconstructed with high efficiency and very low background contamination. In addition, the polarisation and spin correlations have been studied, exploiting the weak, self-analysing decay of hyperons and antihyperons. Two independent approaches to the finite efficiency have been applied and evaluated: one standard multidimensional efficiency correction approach, and one efficiency independent approach. The applicability of the latter was thoroughly evaluated for all channels, beam momenta and observables. The standard method yields good results in all cases, and shows that spin observables can be studied with high precision and accuracy already in the first phase of data taking with PANDA., Comment: 26 pages, 16 figures. Changes: Revised title and abstract and corrections/clarifications in the text according to suggestions by journal referees

Developing metrology solutions is of major importance when building data-measurement systems. One of the key issues is evaluating the characteristics of measuring channels built on the basis of digital sensors of physical values. These sensors include a primary analog transducer and an analog-digital converter. The study evaluates the occurrence of errors in measuring channels of a multi-channel data-measurement system. This study deals with the measuring channel built on the basis of digital temperature sensor employing contact measurement. The digital temperature sensor is an integral body that combines both the primary temperature transducer and the primary data processing units. Drawing on the analysis of various errors the study develops the abstract metrology model of the measuring channel. This model takes into account the errors related to inherent instrument errors as well as the errors induced by the structure of the measuring subsystem. The work presents calculations of multiplicative and additive errors of the measuring channel. It also suggests measures for minimizing the additive errors of the measuring channel in the system.

In the article the features of dynamic plate bending, as a basis of printed board assemblies of onboard radio-electronic equipment, with its resonance oscillations and various fixing conditions, are analyzed. Application features of the bending mode for solving the problem of radio elements placing on the plate field are considered. Methods for obtaining the eigenmodes of the plate by mathematical and experimental methods are described. An idea of adaptive control of oscillations of the plate in the resonant mode is proposed.

Based on the properties of Huygens elements, a solution for determining the electric component strength of the electromagnetic field, taking into account the influence of a reflective surface of a complex shape, is proposed. The paper uses the application of geometrical optics method for the case when the length of the electromagnetic wave is comparable with dimensions of its reflection surface. To represent the complex shape of the reflective surface of objects, the decomposition method is used, where each section of the partition has the properties of the elementary Hertzian electric dipoles. The calculated expressions for the main planes of the Cartesian coordinate system are obtained, allowing us to determine the strength of the electric component of the electromagnetic field as a result of reflection, taking into account the amplitudes and phases from each elementary surface section of the complex shape. The developed method allows determining the strength of the electric component of the electromagnetic field as a result of reflection, taking into account amplitudes and phases from each elementary surface section of the complex shape, correctly divided into rectangular surfaces of reflection with optimally chosen dimensions. In addition, the directional properties of the reflective surface are functionally described, being an advantage in searching for effective design solutions in the process of developing radio-electronic means for various purposes.

Neuropsychological research methods are used to evaluate cognitive functions (CF). Tests used in clinical neuropsychology, in most cases, describe one or more aspects of cognitive domains that are theoretical «constructs» in which several cognitive processes are involved. Neuropsychological tests measure CFs regardless of the medical condition of the test subject. This allows for determination of even minor changes in CFs, including in clinical trials, which is of fundamental importance in studying the efficacy and safety of a given therapy. This article deals with specific aspects of using neuropsychological and screening testing of cognitive functions in individual domains on the basis of foreign experience. It discusses the criteria for selection and application of individual tools, their features, and choice of criteria for evaluating the results of testing in clinical studies in cases of CFs deterioration in various medical conditions accompanied by cognitive impairment. When planning clinical trials, it should also be taken into account that mixed anxiety-depressive disorders are likely to cause forgetfulness, and this calls for differential diagnosis and should be registered in clinical research protocols. The use of subscales and combinations of components of different tools are encouraged based on the objectives of the clinical study, and the tools of neuropsychological research and cognitive function assessment should be validated taking into account the specificity and sensitivity of the method, using statistical analysis methods for specific purposes and tasks. Such a multifaceted approach to the study of cognitive impairments will significantly increase the level of clinical trials conducted and, consequently, will make it possible to put up for sale efficacious and safe medicines for the treatment of cognitive impairment.

The Government of the Russian Federation approved the State strategy of combating the spread of HIV aimed at prevention of HIV epidemic. One of the goals of the Strategy is to increase the coverage of antiretroviral therapy for people infected with HIV, which includes extensive use of generic drugs. In order for a generic drug to be authorised, the applicant has to submit a report on the results of the bioequivalence studies in which the generic product was compared to the reference product. Atazanavir is an antiretroviral drug, which is also the drug of choice for the treatment and prevention of mother-to-child transmission of HIV. The aim of this study was to analyze the protocols and reports of atazanavir products bioequivalence studies, which were submitted for expert examination to the FSBI “SCEEMP” of the Ministry of Health of the Russian Federation, and to prepare recommendations for planning of bioequivalence studies of atazanavir products. The analysis of a number of studies revealed significant differences in the study design and number of subjects. The main reason for these differences is the conflicting data on the intrasubject coefficient of variation of atazanavir, which means that atazanavir may be considered a highly variable drug. The analysis helped to formulate recommendations for the design of bioequivalence studies of atazanavir products, including studies of the maximum dose, studies under fed conditions, and consideration of atazanavir variation when planning the study design.

Rheumatoid arthritis (RA) is an autoimmune rheumatic disease of unknown etiology which manifests itself in chronic erosive arthritis (synovitis) and systemic lesions affecting internal organs. The main emphasis in the RA treatment is placed on the pharmacological therapy: non-steroidal anti-inflammatory drugs, ordinary analgesics, glucocorticoids, basic synthetic anti-inflammatory drugs, and targeted therapy drugs which are now represented by genetically engineered biologicals. The choice of rational treatment options for this severe disease is an important challenge facing modern medicine. The study reported in this paper analysed the clinical data registry for basic anti-inflammatory drugs for RA treatment, which was elaborated based on RA classification and diagnostic criteria. It was revealed that a product’s indications for use are formulated in the clinical data registry based on the product’s pharmacological properties and are accompanied with the description of the target population. It is necessary to provide a list of clinical parameters that will be monitored in the study to demonstrate the efficacy of treatment. The main efficacy endpoint may be chosen based on the product’s pharmacological properties. The efficacy is assessed using integrated indicators. Expected endpoints should be in line with the declared indication for use. Trials that confirm efficacy of a product should assess its therapeutic potential to the fullest extent possible. Before a medicinal product is authorised, it is necessary to obtain sufficient data on its safety, taking into account potential risks of long-term use.

Planning issues for darunavir (DRV) bioequivalence studies are considered. DRV is an antiviral (HIV) agent classified as an HIV protease inhibitor. Bioequivalence test results must be submitted for registration of generic drugs in the RF according to Federal Law 61-FZ. Bioequivalence study protocols and reports for DRV preparations that were submitted for review to the SCEEMP were analyzed. Differences in study designs including administration after fasting or meals, with or without a low dose of ritonavir, numbers of volunteers included in the study, and intra-subject variability were found. The internet was also searched for data on DRV variability. Recommendations for planning bioequivalence studies of DRV preparations were formulated based on the analysis.

Literature data and domestic and foreign methodological documentation for preclinical studies of the safety and toxicokinetics of pharmaceuticals are analyzed. According to Marketing Authorization and Assessment Rules for Medicinal Products in the EAEU, a developer must include in a General Technical Document information on toxicokinetic studies that is evaluated during a review of preclinical test results. The main approaches to expert evaluation of drug toxicokinetic studies are formulated. The main content of the expert analysis includes the methodological basis and results of the research, safety profile characteristics, extrapolation of preclinical data, risk factor characteristics, and predicted clinical patient safety profile. The inclusion of toxicokinetic studies in a program of preclinical toxicological studies is important in principle for an adequate extrapolation of experimental data and prediction of the safety of pharmaceuticals in humans. Expert analysis of toxicokinetic data allows toxicology study results, drug toxicity profile characteristics, and the risk of toxic side effects to be interpreted correctly.

50 keV 64Zn+ ions to a dose of 5 × 1016 cm–2 are implanted into substrates of single-crystal n-type silicon. Then the samples are irradiated at room temperature with 167 MeV 132Xe26+ ions with a fluence ranging from 1 ×1012 up to 5 × 1014 cm–2. Changes in the structure and properties on the sample surface and in its body are studied by scanning electron microscopy, energy dispersive microanalysis, atomic force microscopy, time-of-flight secondary ion mass spectrometry, and photoluminescence.

Background. Evidence of the effect of sex on the pharmacokinetics of drugs and, accordingly, on the clinical response is significantly accumulated, because of a growing number of clinical studies of the early development of original drugs, which include female subjects. The number of bioequivalence studies of replicated drugs involving both sexes is also growing. Of particular importance for the bioavailability of oral medications are differences in the anatomy and physiology of the digestive system. Along with this factor, the differences may be due to the dosage form of the reproduced drug, which may differ from that of the reference (original). The aim of the study was to identify the effect of sex differences on the pharmacokinetics of drugs and to propose an algorithm for assessing their detection. Materials and methods. The article presents a general analysis of the works devoted to the pharmacokinetics of medicines in men and women and includes literature data. Results. The main factors influencing the pharmacokinetics of drugs (absorption, distribution, metabolism, excretion) are identified. Examples of medicinal products for which differences in pharmacokinetics in men and women are revealed are given. The article describes the main international requirements for conducting clinical trials and bioequivalence studies with regard to the choice of gender of subjects and their number to be included in the clinical study. It is suggested that there is a need to further study of the effect of sex differences on bioequivalence results in carrying out relevant studies. Conclusion. An algorithm for estimating the detection of sex differences and their effect on the results of bioequivalence studies of generic drugs is proposed.

The results of studying the surface Si layer and precipitate formation in CZ n-Si(100) samples sequentially implanted with 64Zn+ ions with a dose of 5 × 1016 cm2 and energy of 100 keV and 16O+ ions with the same dose but an energy of 33 keV at room temperature so that their projection paths Rp = 70 nm would coincide are presented. The post-implantation samples are annealed for 1 h in an inert Ar medium in the temperature range of 400–900°C with a step of 100°C. The profiles of the implanted impurities are studied by time-of-flight secondary ion mass spectrometry. The Si surface is visualized using a scanning electron microscope, while the near-surface layer is visualized with the help of maps of elements formed by Auger electron spectroscopy with profiling over depth. The ZnO(002) texture is formed in an amorphized Si layer after the implantation of Zn and O ions. ZnO(102) crystallites of 5 nm in size are found in a recrystallized single-crystalline Si layer after annealing in Ar at 700°C.

The article analyses regulatory documents and requirements for statistical principles of planning and evaluation of results of bioequivalence studies. It describes current statistical approaches to bioequivalence evaluation and relevant recommendations for the planning of studies of conventional medicinal products, medicinal products with a narrow therapeutic range, and analogues of endogenous compounds. The article analyses such statistical approaches as average Bioequivalence (ABE), Average Bioequivalence with Expanding Limits (ABEL), Reference-Scaled Average Bioequivalence (RSABE). It describes specific aspects of statistical analysis of insufficiently studied medicinal products. The article also describes acceptable algorithms of planning and performing two-stage bioequivalence study designs, since such studies call for multiple testing of the bioequivalence hypothesis which leads to an increased probability of type i error (consumer risk). The article offers recommendations for the choice of statistical approaches and describes some aspects of statistical analysis methods depending on the design of the study and the type of generic medicines.

The 64Zn+ and 16O+ ions were implanted in SiO2 film on Si substrate with next parameters: the implant dose was 5.0 × 1016 cm–2, for Zn+ ions the energy was 50 keV and for O+ ions the energy was 16 keV. Than the samples were subjected to isochronally during 1h annealing in N2 atmosphere in temperature range 400–600°C and than in Ar atmosphere in temperature range from 700 up to 1000°C with a step of 100°C. After annealing the samples surface is structured and its roughness increases due to nanoparticle formation in subsurface layer. In as implanted and in annealed samples on its surface and in its body the Zn-contained nanoparticles with a size about 100 nm were formed. These nanoparticles consist presumably from Zn phase after implantation and from ZnO phase after annealing.

Expansion of the range of new medicines leads to a significant increase in healthcare spending and, consequently, to the appearance of more affordable generic drugs. A drug can be recognised as generic if there is sufficient evidence of equivalent structural characteristics of the active substance and therapeutic characteristics of the drug. However, for a number of substances which are multicomponent mixtures of sister compounds it is quite difficult to demonstrate absolute similarity of the chemical structure and to determine a substrate for bioavailability evaluation. Therefore, a separate group of non-biological complex drugs has been singled out. The present article summarises the requirements of the leading regulatory agencies for demonstration of equivalence between the reference product and such medicines as glatiramoids, liposome-encapsulated doxorubicin and iron-based nanosized colloidal products. It has been shown that preclinical and clinical studies are still necessary for these types of products, and the amount of testing will depend on the results of comparability assessment.

The article demonstrates that bioequivalence studies of generic drugs whose active substances are analogues of endogenous compounds found in the human body in natural concentrations present a major challenge as compared to other products and call for a specific regulatory approach. In the absence of available scientific data demonstrating that the product intake can increase the general concentration of the endogenous compound, conducting bioequivalence studies can be economically impractical in contrast to a standard comparative clinical trial, because first it would be necessary to demonstrate a significant increase in the compound concentration in blood plasma. The article analyses Russian legislation and international law with respect to evaluation of medicinal products that are analogues of endogenous compounds, i.e. vitamins, hormones, enzymes, amino acids and salts. It was demonstrated that correction for endogenous compound concentration in blood plasma and control of its dietary intake are required in order to obtain accurate bioequivalence results. The article summarises the experience gained at the FSBI «SCEEMP» of the Ministry of Health of the Russian Federation with respect to evaluation of medicines that are analogues of endogenous compounds, and outlines the most frequent mistakes in testing protocols. It substantiates the need for an individual approach tailored for each particular product, since there is no single solution to the problem of background concentration of endogenous compounds. The authors of the article developed some key solutions that can help minimize the impact of background concentrations of test samples on the results of bioequivalence assessment. Based on the results of the analysis performed and accumulated experience the authors of the article suggested some ways to resolve the problem.

The article reviews literature data on development and clinical use of biomedical cell products (BCPs) — a new class of medicines which could be approved for distribution and use only after their specific activity and safety have been thoroughly examined at the stage of experimental research. The article describes main characteristics of BCPs approved in the Russian Federation, as well as specific aspects of their formulation and use. It analyses the main stages of preclinical studies (requirements for animal models, testing of general toxicity, immunogenicity, oncogenicity, tumorigenicity, etc.) that do not cover medicine quality evaluation. The article also dwells upon requirements for the clinical stage of BCPs development. It was shown that the choice of clinically relevant efficacy and safety endpoints could be substantiated by respective preclinical data and accumulated experience of the clinical use of medicines for a particular condition.

The influence of Zn ions implanted in a sapphire single crystal on the kinetics of attainment of the equilibrium state of the surface potential and current characteristics is considered. To consider the influence of the surface state on the dielectric charging process, one of the samples is annealed in an oxygen atmosphere to form ZnO on the surface. The obtained results show a significant increase in the rate of attainment of the equilibrium surface potential after ion implantation. To understand the obtained results, the dependence of the concentration of the doping impurity as a function of the crystal depth is measured. The possible mechanisms affecting a change in achievement of the potential are discussed.

Since Ilya Metchnikoff’s studies, both medical science and clinical practice have accumulated a large amount of evidence that human intestinal microbiota possesses a unique characteristics for our existence. However, only recently, scientists have achieved the actual breakthrough in this field of human physiology, and we start to understand the precise mechanisms of the complex interplay of microbial activity with human homeostasis and discover numerous new functions of intestinal microbes. In this regard, a novel medical technology evolves since 1958, so called fecal microbiota transplantation (FMT), which is the administration of donor feces to the patients suffering from different kinds of diseases. Such infusion of donor feces restores the natural balance of gut commensal germs. FMT is most efficacious in severe or recurrent Clostridium difficile infection. FMT has been also reported to cure diarrhea and constipation caused by different conditions, such as multiple sclerosis, Crohn ’s disease etc. In the U.S. and Canada as well as in other countries FMT is of uttermost interest of not merely clinical practitioners but lately also of regulatory authorities. The paper also addresses the possibility of application the Russian pharmaceutical legislation to FMT.

The article analyses regulatory documents containing requirements for clinical (trials) documentation for orally inhaled products, including requirements for the demonstration of therapeutic equivalence of medicinal products for the treatment of bronchial asthma and chronic obstructive pulmonary disease in adults and children. The article summarises the main approaches to the assessment of inhalers equivalence. It also systematizes and describes dosage forms and inhalation devices, as well as the necessary stages of inhaler evaluation, looks into the methodology of conducting therapeutic equivalence studies with due regard to the therapeutic class of the drug, duration of its action and proposed nosology. The methodology includes requirements for the selection of the study population, study design and conditions, and recommendations for the selection of drug dose, study duration, primary and secondary efficacy and safety endpoints in the context of orally inhaled products.

The article reviews scientific literature on the conduct of in vivo pharmacokinetic studies of drugs that are similar to endogenous compounds. It summarises approaches to pharmacokinetic evaluation of calcium drugs. It was demonstrated that the pharmacokinetic evaluation of drugs containing calcium ions in the form of various salts requires assessment of several parameters: parameters indicative of calcium absorption (Cmax and AUC with due regard to baseline concentrations of endogenous calcium), homeostatic mechanisms which regulate the concentration of this endogenous compound (calcium excretion parameters) and hormonal regulation of phosphate and calcium homeostasis (parathyroid hormone).

The article discusses the design of development programmes for biosimilars used to treat patients with rheumatic diseases. It analyses the most popular definitions of biosimilars that are used in Russia and abroad, as well as regulatory approaches to establishing biosimilarity. The authors describe the design of confirmatory clinical trials and draw attention to the fact that equivalence margins need to be justified on both clinical and statistical grounds. The article substantiates the need to continuously improve the requirements for and approaches to the assessment of the programmes’ applicability to biosimilars evaluation.

The article substantiates approaches to evaluation of results obtained in preclinical safety pharmacology studies. It describes historical background for the development of regulatory requirements and methodological recommendations for performance of such studies, provides a classification of various types of safety pharmacology studies, lays down general requirements for examination of the main battery of tests as well as subsequent and additional tests, examines the aims and main tasks of such studies, and cites examples of tests. The authors define the main scope of expert evaluation which includes the methodological basis of studies, results of studies, characterisation of a medicine’s safety profile, interpretation of preclinical data, assessment of risk factors and an anticipated clinical safety profile for patients.

The article reviews bioequivalence studies of Russian and foreign generic rosuvastatin preparations with the goal of harmonizing approaches to rosuvastatin bioequivalence studies in the Russian Federation. The article describes the current regulatory recommendations for and approaches to bioequivalence studies of generic drugs (and in particular of rosuvastatin preparations which are highly variable drugs) and gives recommendations on the design of rosuvastatin studies and evaluation of results.

At present a specific group of medicines - highly variable medicines - is distinguished based on intraindividual variability data (CVintra > 30%). It is quite difficult to confirm therapeutic equivalence of highly variable medicines by pharmacokinetic bioequivalence studies, and quite a large number of subjects need to be included into the study in order to confirm bioequivalence within standard limits of 80-125%. Variability may be caused by many factors which include physiological and pathophysiological differences in absorption and metabolism processes; factors associated with properties of the active substance and factors associated with the finished product. In general factors impacting variability in bioequivalence studies could be divided into controllable and uncontrollable. The influence of controllable factors can be neutralized by proper performance of the bioequivalence study or proper development of the finished product. The influence of uncontrollable factors cannot be neutralized, and due to these factors medicines can be recognized as highly variable. This article provides a definition of a highly variable medicine, describes reasons for high variability and outlines current regulatory recommendations for and approaches to studying bioequivalence of highly variable medicines, proposes recommendations for designing such studies.

The main results of tests performed on VVER-1000 fuel elements with high burnup of fuel in a channel of the MIR channel reactor for LOC accident conditions are examined. The experimental setup contains one fuel element, which is arranged along the central axis. The aim of the tests is to determine the parameters of cladding depressurization. In the experiment, questions concerning fragmentation, axial displacement, and possible escape of fuel to outside the cladding were studied and the properties of the cladding material and fuel, which were subjected to the extreme parameters, were determined. The main parameters and the results of two experiments are presented. The conditions under which fuel-element depressurization occurred are determined.

Issues pertaining to determination of the pharmacokinetic parameters of calcium preparations are examined using their comparative bioavailability as an example. Pharmacokinetic parameters of calcium such as area under the concentration—time curve (AUC) and maximum concentration (Cmax) are calculated considering the background calcium contents in volunteers. Calcium excretion with urine is assessed as clearance of creatinine, a calcium elimination factor. The dynamics of the content of parathormone (PTH), the main hormone regulating calcium homeostasis, are studied. The results can be used to plan clinical trials for assessing the pharmacokinetics of drug analogs of endogenous compounds.

The cross section of atomic electron Compton scattering $\gamma + e \rightarrow \gamma^\prime + e^\prime $ was measured in the 4.40--5.475 GeV photon beam energy region by the {\em PrimEx} collaboration at Jefferson Lab with an accuracy of 2\% and less. The results are consistent with theoretical predictions that include next-to-leading order radiative corrections. The measurements provide the first high precision test of this elementary QED process at beam energies greater than 0.1 GeV., Comment: 6 pages, 4 figures

The problem of the analysis of project documentation are considered. Various ways of presenting documentation are described. The task of finding frequent subgraphs is presented. An algorithm for searching for documentation based on the search for frequent subgraphs is proposed.

The features of the computer-aided design process are considered. A model of processes in CAD based on the modification of Petri nets is presented. A discrete event model of a typical design procedure is described.

The article describes an adaptive technique for vibration testing to determine dynamic characteristics of structural elements of new generation rocket-space and aviation technology. A technique for experimental determination of centers of natural mode antinodes of the object studied is proposed. An algorithm for the formation of the test signal has been developed. A structure of an adaptive intelligent vibration testing system has been developed.