[PLANNING THE DESIGN AND ESTIMATING THE RESULTS OF INVESTIGATIONS OF BIOEQUIVALENCE OF HIGHLY VARIABLE DRUGS BY EXAMPLE OF ROSUVASTATIN].

The article gives a definition of highly variable drugs, describes currently existing regulatory guidance and approaches to the study of bioequivalence of highly variable drugs, and formulates recommendations on the design and evaluation of the results of studies of such drugs. These aspects are considered by the example of calculations based on actual data from the registration dossiers materials for rosuvastatin.

[JUSTIFICATION OF USING EQUIVALENCE OF THE INDICES OF QUALITY, SAFETY, AND EFFICACY IN DEVELOPING BIOANALOGS].

We describe general principles of demonstrating biosimilarity, as well as selecting the biosimilarity margins. Any change in the structure of a biological molecule can modify its functional activity. Therefore, therapeutic equivalence between a biosimilar product and the corresponding reference product cannot be demonstrated using a single criterion. To demonstrate biosimilarity between two medicinal products, their various characteristics have to be evaluated which may, directly or indirectly, justify that clinically significant differences are absent. Insufficient understanding of 6ritical quality attributes brings a risk for the biosimilar product developer. This will either increase the number of non-clinical and clinical tests and trials needed or will result in awareness that the manufacturing process needs to be improved at the late stages of development, after investing significant resources in the development process. At the same time, the specification of the biological medicinal product cannot solely ensure safety and efficacy thereof. Properly characterized and controlled manufacturing process, which ensures consistency in its attributes not adequately controlled in specifications but influencing safety and efficacy profiles and showing their relevance in non-clinical tests and clinical trials, is an additional quality assurance factor. Justification of all development strategy details, including biosimilarity margins, has to be provided each time when the development process is initiated or when proceeding to the next steps. All problems encountered by the developer have to be resolved in close communication with the regulatory authority. In order to increase the quality of investigation and developer's adherence to good practices, clinical trial results should be published in detail.

[GOOD PLANNING PRACTICE IN PRECLINICAL AND CLINICAL STUDIES OF UNFRACTIONATED AND FRACTIONATED HEPARINS IN RUSSIA AS THE BASIS OF SAFE AND EFFECTIVE ANTICOAGULATION THERAPY].

General principles of appropriate strategies for preclinical and clinical development of unfractionated and low-molecular-weight heparins and demonstration of their biosimilarity to corresponding reference medicinal products are provided. Demonstration of the biosimilarity of heparin-containing medicinal products constitutes the basis for their efficacy and safety during anticoagulation therapy. The main quality, safety, and efficacy characteristics of heparin products are described and the extent of non-clinical and clinical investigations necessary prior to drug marketing authorization are considered.

[Demonstration of quality, safety and efficacy of biological products subject to changes in their manufacturing process].

Ensuring quality, safety and efficacy of the medicinal products placed on the market of the Russian Federation constitutes the area that requires strict regulation. When changes are made to the manufacturing process, the manufacturer generally needs to evaluate the relevant quality attributes of the product to demonstrate that modifications did not occur that would adversely impact the safety and efficacy of the drug. Where there is the lack of a sound legal basis, there is a need in harmonization of current Russian legislation with international and European rules governing medicinal product for human use to ensure quality, safety and efficacy thereof.

[A clinicoeconomic model of basic therapy for bronchial asthma].

The paper is dedicated to analysis of the most wide-spread variants of bronchial asthma (BA) basic therapy. The analysis was based on the results of a large (1362 patients from 34 Russian cities) pharmacoepidemiological study. Different models of pharmacotherapy were assessed on the basis of clinical data (the frequency of symptoms), the risk of BA exacerbation, the volume of public health resources used, and the cost of treatment. The results of the study showed that the use of set combinations of inhaled glucocorticosteroids and long-acting , beta2-adrenostimulators was most effective and rational from economic perspective under real clinical conditions.