Specific Aspects and Significance of Subgroup Assessment in Confirmatory Clinical Trials

Patient subgroup analysis plays an important role in interpretation of confirmatory clinical trial results and is mandatory in most cases. The purpose of subgroup analysis is to assess the consistency (heterogeneity) of the treatment effect in subgroups of patients identified based on such characteristics as demographics, stage and severity of the underlying disease, presence of a certain genetic mutation, etc. However, existing methodological issues (the problem of multiple comparisons, detection of differences between subgroups by chance alone, etc.) make it difficult to carry out the analysis and often lead to controversial conclusions. The aim of  the study was to analyse and summarise foreign regulatory approaches to subgroup analysis in confirmatory clinical trials, and to elaborate science-based requirements for subgroup analysis and interpretation of the results by clinical trial sponsors and experts when assessing the risk-benefit ratio of medicinal products for the purpose of their authorisation in Russia and the  Eurasian Economic Union. This paper discusses the objectives of subgroup  analysis and statistical approaches to its performance, provides relevant examples of such analysis from regulatory practice. It describes approaches to interpretation of subgroup analysis depending on the presence/absence of evidence supporting the primary hypothesis of the study, the nature of the experimental medicinal product’s heterogeneous effects in the  subgroups, and selection of the subgroups. The paper highlights areas of concern in subgroup analysis, potential controversies in interpretation of the  obtained results, and regulatory expectations. The recommendations  presented in the paper can be used by experts in the assessment of the risk-benefit ratio, as well as by medicine developers in the preparation of clinical trial protocols and reports

Регуляторные подходы к программе разработки лекарственных препаратов, применяемых для лечения инфекционных заболеваний

In February 2017 the World Health Organization first published the list of antibiotic-resistant «priority pathogens» — a catalogue of 12 species of bacteria that pose the greatest threat to human health. The list highlights the danger posed by Gramnegative bacteria that are resistant to multiple antibiotics. Thus, the development of new antimicrobial medicines is becoming a pressing issue. The list is an important reference point and incentive to secure and guide research and development related to new antibiotics that will help solve the issue of growing global resistance to antimicrobial medicines. The aim of the study was to determine the main regulatory approaches to planning preclinical and clinical development programmes for new antimicrobial medicines. On the basis of current requirements and recommendations in force in the Russian Federation and guidelines of the European Medicines Agency, the issues of planning antimicrobial drug development programs were considered. The autors analysed the main stages and aspects of preclinical studies of medicines for infectious diseases (specific activity in vitro and in vivo, PK-PD modeling), as well as requirements for the clinical trial stage, including the rationale for the choice of clinically relevant efficacy and safety endpoints, study design, and statistical methods.Всемирная организация здравоохранения в феврале 2017 г. впервые опубликовала документ, содержащий перечень устойчивых к действию антибиотиков «приоритетных патогенов» — 12 видов бактерий, которые представляют наибольшую угрозу для здоровья человека. В документе подчеркивается опасность, которую представляют грамотрицательные бактерии, устойчивые к действию сразу нескольких антибиотиков. В связи с этим очевидна актуальность разработки новых антибактериальных препаратов, а данный документ призван стать ориентиром и стимулом для научных исследований и разработок в области создания новых антибиотиков, которые помогут в решении масштабной проблемы устойчивости к противомикробным препаратам. Цель работы — определение основных регуляторных подходов к планированию программы доклинических и клинических исследований новых антимикробных препаратов. На основании актуальных требований и рекомендаций, действующих в Российской Федерации, и руководств Европейского агентства по лекарственным средствам, рассмстрены вопросы планирования программ разработки антибактериальных препаратов. Проанализированы основные этапы и особенности проведения доклинических исследований лекарственных препаратов, применяемых для лечения инфекционных заболеваний (специфическая активность in vitro и in vivo, фармакокинетическое-фармакодинамическое моделирование). Рассмотрены требования, предъявляемые к этапу клинических исследований данной группы препаратов, включая обоснование выбора клинически значимых конечных точек оценки безопасности и эффективности, дизайна исследования, статистического расчета

Особенности и значимость оценки подгрупп в подтверждающих клинических исследованиях

 Patient subgroup analysis plays an important role in interpretation of confirmatory clinical trial results and is mandatory in most cases. The purpose of subgroup analysis is to assess the consistency (heterogeneity) of the treatment effect in subgroups of patients identified based on such characteristics as demographics, stage and severity of the underlying disease, presence of a certain genetic mutation, etc. However, existing methodological issues (the problem of multiple comparisons, detection of differences between subgroups by chance alone, etc.) make it difficult to carry out the analysis and often lead to controversial conclusions. The aim of  the study was to analyse and summarise foreign regulatory approaches to subgroup analysis in confirmatory clinical trials, and to elaborate science-based requirements for subgroup analysis and interpretation of the results by clinical trial sponsors and experts when assessing the risk-benefit ratio of medicinal products for the purpose of their authorisation in Russia and the  Eurasian Economic Union. This paper discusses the objectives of subgroup  analysis and statistical approaches to its performance, provides relevant examples of such analysis from regulatory practice. It describes approaches to interpretation of subgroup analysis depending on the presence/absence of evidence supporting the primary hypothesis of the study, the nature of the experimental medicinal product’s heterogeneous effects in the  subgroups, and selection of the subgroups. The paper highlights areas of concern in subgroup analysis, potential controversies in interpretation of the  obtained results, and regulatory expectations. The recommendations  presented in the paper can be used by experts in the assessment of the risk-benefit ratio, as well as by medicine developers in the preparation of clinical trial protocols and reports.  Анализ подгрупп пациентов играет важную роль в интерпретации результатов подтверждающих клинических исследований и в большинстве случаев обязателен к выполнению. Целью анализа является оценка согласованности (гетерогенности) терапевтического эффекта в подгруппах пациентов, выделенных на основании  демографических характеристик, стадии и степени тяжести основного  заболевания, наличия определенной генетической мутации и др. Однако существующие методологические проблемы (проблема  множественных сравнений, случайные различия между подгруппами и т.д.) затрудняют его проведение и часто приводят к спорным выводам.  Цель работы — анализ и систематизация подходов зарубежных  регуляторных органов к оценке подгрупп в подтверждающих  клинических исследованиях, формирование научно обоснованных  требований к ее выполнению и интерпретации результатов спонсорами клинических исследований и экспертами при проведении экспертизы  отношения ожидаемой пользы к возможному риску применения лекарственных препаратов с целью их регистрации по национальным  правилам и по правилам Евразийского экономического союза. В работе  рассмотрены цели проведения анализа подгрупп и статистические  подходы к его выполнению, приведены примеры такого анализа из регуляторной практики. Описаны подходы к интерпретации анализа подгрупп в зависимости от наличия или отсутствия доказательства  основной гипотезы исследования, характера обнаруженных  гетерогенных эффектов исследуемого препарата в подгруппах и выбора  самих подгрупп. Освещены проблемные аспекты анализа подгрупп, возможные противоречия интерпретации полученных результатов,  регуляторные ожидания. Представленные рекомендации могут быть  использованы экспертами при проведении экспертизы  отношения ожидаемой пользы к возможному риску применения лекарственного  препарата, а также разработчиками лекарственных средств при подготовке протоколов и отчетов клинических исследований.

Use of a neural network in creating a digital assistant for blind and visually impaired people

The experience of ongoing research in image processing clearly demonstrates the huge scope for the development of new neural networks that can help people in a wide range of tasks. The authors chose the direction of work related to helping people who have vision problems. The article considers a convolutional neural network of the Mask R-CNN model for segmenting objects in an image. During the research the authors study a large number of algorithms that can quickly and accurately process images, such as Faster R-CNN, which was the most efficient in 2020. During the analysis, it was revealed that the use of Mask R-N technology can significantly increase the efficiency of performing tasks, since this algorithm is the latest version of the machine learning model. As a result of the study, a neural network was developed that is capable of identifying and distinguishing a large number of objects in an image. The next step is to refine the algorithm and use additional means of interaction with the hardware of the systems to increase the speed of the neural network. In the future, the resulting neural network will be integrated into the Digital Assistant for the Blind and Visually Impaired Persons application. This application is guaranteed to improve the daily life of people with disabilities who experience certain inconveniences due to their features, and can become the basis for other, larger projects related, for example, to unmanned devices, as well as services whose work is directly based on image processing

Phosphatidylserine Targets Single-Walled Carbon Nanotubes to Professional Phagocytes In Vitro and In Vivo

Broad applications of single-walled carbon nanotubes (SWCNT) dictate the necessity to better understand their health effects. Poor recognition of non-functionalized SWCNT by phagocytes is prohibitive towards controlling their biological action. We report that SWCNT coating with a phospholipid “eat-me” signal, phosphatidylserine (PS), makes them recognizable in vitro by different phagocytic cells - murine RAW264.7 macrophages, primary monocyte-derived human macrophages, dendritic cells, and rat brain microglia. Macrophage uptake of PS-coated nanotubes was suppressed by the PS-binding protein, Annexin V, and endocytosis inhibitors, and changed the pattern of pro- and anti-inflammatory cytokine secretion. Loading of PS-coated SWCNT with pro-apoptotic cargo (cytochrome c) allowed for the targeted killing of RAW264.7 macrophages. In vivo aspiration of PS-coated SWCNT stimulated their uptake by lung alveolar macrophages in mice. Thus, PS-coating can be utilized for targeted delivery of SWCNT with specified cargoes into professional phagocytes, hence for therapeutic regulation of specific populations of immune-competent cells

Regulatory Approaches to the Development Programme for Medicines Used to Treat Infectious Diseases

In February 2017 the World Health Organization first published the list of antibiotic-resistant «priority pathogens» — a catalogue of 12 species of bacteria that pose the greatest threat to human health. The list highlights the danger posed by Gramnegative bacteria that are resistant to multiple antibiotics. Thus, the development of new antimicrobial medicines is becoming a pressing issue. The list is an important reference point and incentive to secure and guide research and development related to new antibiotics that will help solve the issue of growing global resistance to antimicrobial medicines. The aim of the study was to determine the main regulatory approaches to planning preclinical and clinical development programmes for new antimicrobial medicines. On the basis of current requirements and recommendations in force in the Russian Federation and guidelines of the European Medicines Agency, the issues of planning antimicrobial drug development programs were considered. The autors analysed the main stages and aspects of preclinical studies of medicines for infectious diseases (specific activity in vitro and in vivo, PK-PD modeling), as well as requirements for the clinical trial stage, including the rationale for the choice of clinically relevant efficacy and safety endpoints, study design, and statistical methods

POSSIBLE WAYS OF REORGANIZING PRIMARY HEALTH CARE IN GYNECOLOGY IN THE LIGHT OF EFFECTIVE EARLY DIAGNOSIS OF REPRODUCTIVE SYSTEM CANCER

The oncological care system, established in Russia as early as the mid-twentieth century, is presently unable to provide an effective early diagnosis of malignancies, including reproductive system tumors. The past 10-15 years have become the years of missed oppor- tunities and losses to a greater extent than modernization of a primary obstetric and gynecological care system. This paper deals with this problem and a search for its solution