World practice of providing scientific advice on the development and authorisation of innovative medicines

Current challenges to healthcare, i.e. the emergence of new diseases, lack of therapies for known diseases and life-threatening conditions, identification of patients who do not respond to standard treatment, on the one hand, and the evolution of scientific understanding of disease processes, medicines, therapies, causes of treatment failures, and implementation in clinical practice of innovations related to molecular biology and genetic engineering, on the other hand, create conditions and opportunities for the development of innovative medicinal products. A relatively new class of medicines is based on human cells and tissues (the term used in Russian legislation is biomedical cell products, BCP). However, the inability to accurately predict the efficacy and financial rewards of such medicines for pharmaceutical companies, as well as significant labour and financial costs associated with their development and clinical use, hinder their entry into the market. The aim of the study was to analyse the foreign regulatory setting for the development and launch of human cell- and tissue-based products, as well as approaches of foreign regulatory authorities to scientific advice, which can be drawn upon by the Russian expert authority when providing advice to BCP developers. The paper summarises the results of analysis of regulations establishing the procedure for providing scientific advice by EU, USA, and Russian regulatory authorities, and analyses the advice provided for the human cell- and tissue-based products which are now authorised in the EU and USA. The analysis of advice provided by foreign regulatory authorities shows that the largest number of consultations were given for medicinal products based on genetically modified cells for the treatment of cancer and genetic diseases. The questions were mainly related to the contents of specifications for finished pharmaceutical products, safety evaluation, curtailing of preclinical studies due to the lack of relevant animal/disease models, the number of subjects and efficacy endpoints in clinical studies, assessment of the appearance of replication-competent retroviruses

Gene therapy of neurodegenerative diseases: achievements, developments, and clinical implementation challenges

Neurodegenerative diseases (NDDs) are promising objects for the development of gene therapy products, primarily, due to the possible cause of these diseases (disruption of a gene or several genes), lack of effective therapy, and negative impact on the quality of life of both patients and their families and friends.The aim of the study was to identify trends and challenges in the development and preclinical and clinical studies of gene therapy products for NDDs and to analyse the international experience of expert assessment of the dossier for Zolgensma®, which received a conditional marketing authorisation.According to the analysis of the ongoing studies of gene therapy products for NDDs, the following major challenges arise at preclinical and clinical stages. For animal studies, a particular challenge is to select a disease model, a route of administration, and a target for effective gene therapy for polygenic disorders. For clinical trials, problematic aspects are the selection of a control group, the development of inclusion criteria for patients with a genetic variant that is an indication for a gene therapy product and exclusion criteria for patients with antibodies to this gene therapy product, the selection and justifi cation of a safe therapeutic dose since a gene therapy product can be administered to a patient only once, and the complexity of assessing clinical benefi ts of transgene expression in the human body due to the inaccessibility of brain tissue for analysis. Recent years have witnessed a breakthrough in gene therapy with the introduction of Zolgensma® (Novartis) to the world pharmaceutical market to treat children with spinal muscular atrophy type 1. The article analyses the experience of expert assessment of the marketing authorisation dossier for Zolgensma®, which can be used by drug developers bringing new medicines to the market of the Eurasian Economic Union under conditional marketing authorisation, which implies that the benefi ts of immediate patient access to these medicines will exceed the risks associated with incomplete data on their characteristics

2D Spectroscopy of Candidate Polar-Ring Galaxies: I. The Pair of Galaxies UGC 5600/09

Observations of the pair of galaxies VV 330 with the SCORPIO multimode instrument on the 6-m Special Astrophysical Observatory telescope are presented. Large-scale velocity fields of the ionized gas in H-alfa and brightness distributions in continuum and H-alfa have been constructed for both galaxies with the help of a scanning Fabry Perot interferometer. Long-slit spectroscopy is used to study the stellar kinematics. Analysis of the data obtained has revealed a complex structure in each of the pair components. Three kinematic subsystems have been identified in UGC 5600: a stellar disk, an inner gas ring turned with respect to the disk through ~80degrees, and an outer gas disk. The stellar and outer gas disks are noncoplanar. Possible scenarios for the formation of the observed multicomponent kinematic galactic structure are considered, including the case where the large-scale velocity field of the gas is represented by the kinematic model of a disk with a warp. The velocity field in the second galaxy of the pair, UGC 5609, is more regular. A joint analysis of the data on the photometric structure and the velocity field has shown that this is probably a late-type spiral galaxy whose shape is distorted by the gravitational interaction, possibly, with UGC 5600.Comment: 18 pages, 6 figure

ОСОБЛИВОСТІ ПОРУШЕННЯ СИСТЕМИ ГЕМОСТАЗУ У ХВОРИХ НА КОРОНАВІРУСНУ ІНФЕКЦІЮ

The aim of the work – to analyze the features of hemostasis disorders in patients with coronavirus infection. Materials and methods. 78 medical records of inpatients hospitalized in the Regional Clinical Infectious Diseases Hospital of Kharkiv for the period from May to September 2020 were analyzed. To assess the state of the hemostasis system and the risk of thrombohemorrhagic complications, the level of platelets, fibrinogen, D-dimer, active partial thromboplastic time (APTT), international normalized ratio (INR) was monitored. Results. During the study, disorders of cellular and plasma indicators of hemostasis were analyzed. Patients were divided into groups, depending on the severity of respiratory failure. Coagulation tests were monitored every 48 hours. Conclusion. In patients with moderate severity, disorders of the hemostasis system in the form of hypercoagulation prevailed. Prolonged course of the disease for more than 21 days or in patients with severe, extremely severe course, hypercoagulation changed to hypocoagulation and DIC syndrome occurred. There is a direct relationship with the state of hemostasis and the severity of coronavirus infection.Мета роботи – проаналізувати особливості порушення системи гемостазу у хворих на коронавірусну інфекцію. Матеріали та методи. Проаналізовано 78 медичних карт стаціонарних хворих, госпіталізованих в обласну клінічну інфекційну лікарню м. Харкова за період з травня по вересень 2020 р. Для оцінки стану системи гемостазу та ризику виникнення тромбогеморагічних ускладнень проводили моніторинг рівня тромбоцитів, фібриногену, D-димеру, активного часткового тромбопластинового часу (АЧТЧ), міжнародного нормалізованого відношення (МНВ). Результати дослідження. Під час дослідження були проаналізовані порушення клітинних і плазматичних показників гемостазу. Хворі були поділені на групи, залежно від ступеня тяжкості дихальної недостатності. Моніторинг коагуляційних тестів проводили кожні 48 год. Висновок. У пацієнтів із середнім ступенем тяжкості переважали порушення системи гемостазу у вигляді гіперкоагуляції. Тривалий перебіг хвороби понад 21 добу або у хворих із тяжким чи вкрай тяжким ступенем гіперкоагуляція змінювалася на гіпокоагуляцію та виникав ДВЗ-синдром. Показники гемостазу прямо корелювали зі ступенем тяжкості коронавірусної інфекції

Study of the structure and kinematics of the NGC 7465/64/63 triplet galaxies

This paper is devoted to the analysis of new observational data for the group of galaxies NGC 7465/64/63, which were obtained at the 6-m telescope of the Special Astrophysical Observatory of the Russian Academy of Sciences (SAO RAS) with the multimode instrument SCORPIO and the Multi Pupil Fiber Spectrograph. For one of group members (NGC 7465) the presence of a polar ring was suspected. Large-scale brightness distributions, velocity and velocity dispersion fields of the ionized gas for all three galaxies as well as line-of-sight velocity curves on the basis of emission and absorption lines and a stellar velocity field in the central region for NGC 7465 were constructed. As a result of the analysis of the obtained information, we revealed an inner stellar disk (r ~ 0.5 kpc) and a warped gaseous disk in addition to the main stellar disk, in NGC 7465. On the basis of the joint study of photometric and spectral data it was ascertained that NGC 7464 is the irregular galaxy of the IrrI type, whose structural and kinematic peculiarities resulted most likely from the gravitational interaction with NGC 7465. The velocity field of the ionized gas of NGC 7463 turned out typical for spiral galaxies with a bar, and the bending of outer parts of its disk could arise owing to the close encounter with one of galaxies of the environment.Comment: 20 pages, 6 figure

Генная терапия нейродегенеративных заболеваний: достижения, разработки, проблемы внедрения в клиническую практику

Neurodegenerative diseases (NDDs) are promising objects for the development of gene therapy products, primarily, due to the possible cause of these diseases (disruption of a gene or several genes), lack of effective therapy, and negative impact on the quality of life of both patients and their families and friends.The aim of the study was to identify trends and challenges in the development and preclinical and clinical studies of gene therapy products for NDDs and to analyse the international experience of expert assessment of the dossier for Zolgensma®, which received a conditional marketing authorisation.According to the analysis of the ongoing studies of gene therapy products for NDDs, the following major challenges arise at preclinical and clinical stages. For animal studies, a particular challenge is to select a disease model, a route of administration, and a target for effective gene therapy for polygenic disorders. For clinical trials, problematic aspects are the selection of a control group, the development of inclusion criteria for patients with a genetic variant that is an indication for a gene therapy product and exclusion criteria for patients with antibodies to this gene therapy product, the selection and justification of a safe therapeutic dose since a gene therapy product can be administered to a patient only once, and the complexity of assessing clinical benefits of transgene expression in the human body due to the inaccessibility of brain tissue for analysis. Recent years have witnessed a breakthrough in gene therapy with the introduction of Zolgensma® (Novartis) to the world pharmaceutical market to treat children with spinal muscular atrophy type 1. The article analyses the experience of expert assessment of the marketing authorisation dossier for Zolgensma®, which can be used by drug developers bringing new medicines to the market of the Eurasian Economic Union under conditional marketing authorisation, which implies that the benefits of immediate patient access to these medicines will exceed the risks associated with incomplete data on their characteristics.Нейродегенеративные заболевания (НДЗ) являются одними из перспективных объектов для разработки препаратов генной терапии, в первую очередь ввиду возможной причины их возникновения (нарушение работы гена или генов), отсутствия эффективной терапии, негативного влияния на качество жизни как самого пациента, так и его окружения.Цель работы — анализ направлений и проблем разработки, проведения доклинических и клинических исследований препаратов генной терапии для лечения нейродегенеративных заболеваний, а также изучение зарубежного опыта экспертной оценки регистрационного досье препарата Zolgensma®, получившего условную государственную регистрацию. Анализ проводимых исследований продуктов генной терапии в области НДЗ показал, что основными проблемами являются: в исследованиях на животных — выбор модели заболевания, способа введения, подбор мишени для эффективной генной терапии при заболеваниях, затрагивающих работу нескольких генов; на этапе клинических исследований (КИ) — выбор группы сравнения, разработка критериев отбора пациентов для участия в КИ с учетом наличия генетической мутации, которая является показанием к проведению генной терапии, исключения из КИ пациентов при наличии у них антител к продукту генной терапии, выбор и обоснование безопасной терапевтической дозы вследствие единственного шанса у пациента на введение препарата генной терапии, сложность оценки клинической пользы по экспрессии трансгена в организме у человека вследствие недоступности тканей мозга для анализа. Прорывом последних лет является вывод на мировой фармацевтический рынок препарата генной терапии Zolgensma® (Novartis) для лечения детей со спинальной мышечной атрофией 1 типа. В статье проанализирован опыт экспертной оценки регистрационного досье препарата Zolgensma®, который может быть использован разработчиками в ходе вывода на рынок Евразийского экономического союза лекарственных препаратов по механизму условной регистрации, подразумевающей, что польза от немедленного доступа пациентов к препаратам будет превышать риски, связанные с неполными данными об их характеристиках

Клинические исследования препаратов клеточной терапии: опыт рассмотрения зарубежными регуляторными органами

Currently, the problem of adopting viable human cell-based drugs – biomedical cell products (BCPs) – in medical practice in the Russian Federation includes, among others, lack of experience in clinical trials for such drugs and insufficient expert assessment under the national state registration procedure. In global practice, by the beginning of 2020, there were over 30 cellular therapy products (human cellular- and tissue-based products) known to have undergone clinical trials for sales licenses from regulatory bodies in the United States, European Union, Japan, and South Korea. Most cellular therapy products are intended for treatment of severe orphan diseases and lifethreatening conditions that currently cannot be treated by traditional drugs or methods. The aim of this study is to analyze the global experience in clinical trials for cellular therapy products and also to examine conclusions reached by regulatory authorities with regards to issuance of sales licenses for the products. Particular attention was paid to clinical trials that subsequently led to granting of sales license (state registration). In reviewing such trials, we also focused on the types and number of clinical trials, the number of patients involved in the clinical trials, conclusions made by expert regulatory agencies on the efficacy, safety and risk/benefit ratio. Most of the products were approved for use based on uncontrolled phase II clinical trials. In the clinical trial, apart from the historical group and the placebo-controlled group, there was also a control group that received nothing. The number of patients in most clinical trials was limited, especially for drugs intended for treatment of rare genetic diseases, as well as drugs approved for use in Japan.В настоящее время проблема внедрения в медицинскую практику в Российской Федерации препаратов на основе жизнеспособных клеток человека – биомедицинских клеточных продуктов (БМКП) – включает, в том числе, отсутствие опыта проведения клинических исследований (КИ) таких препаратов и их экспертной оценки в рамках национальной процедуры государственной регистрации. В мировой практике к началу 2020 г. известно более 30 препаратов клеточной терапии (препаратов на основе клеток и тканей человека), которые прошли процедуру рассмотрения результатов клинических исследований в рамках получения разрешения на продажу регуляторными органами США, Европейского союза, Японии, Южной Кореи. Большинство препаратов для клеточной терапии предназначены для лечения тяжелых орфанных заболеваний и жизнеугрожающих состояний, потребность в лечении которых в настоящее время не обеспечена традиционными лекарственными препаратами или методами. Целью данного исследования является анализ мирового опыта проведения клинических исследований препаратов клеточной терапии и рассмотрения регуляторными органами их результатов в рамках получения разрешения на продажу. Особое внимание было уделено КИ, на основе которых препарат получал разрешение на маркетинговую авторизацию (государственную регистрацию): типам и количеству КИ, количеству пациентов, участвующих в КИ, выводам, сделанным экспертами регуляторных органов по эффективности, безопасности и отношению ожидаемой пользы к возможному риску применения этих препаратов. Преимущественно препараты были разрешены к применению на основе неконтролируемых КИ II фаз, в качестве контрольных групп сравнения использовался исторический контроль, плацебо или введение в КИ группы без применения препарата; количество пациентов в большинстве КИ было ограниченным, особенно для препаратов, предназначенных для лечения редких генетических заболеваний, а также препаратов, разрешенных к применению в Японии

Steps Toward Determination of the Size and Structure of the Broad-Line Region in Active Galactic Nuclei. XVI. A Thirteen-Year Study of Spectral Variability in NGC 5548

We present the final installment of an intensive 13-year study of variations of the optical continuum and broad H-beta emission line in the Seyfert 1 galaxy NGC 5548. The data base consists of 1530 optical continuum measurements and 1248 H-beta measurements. The H-beta variations follow the continuum variations closely, with a typical time delay of about 20 days. However, a year-by-year analysis shows that the magnitude of emission-line time delay is correlated with the mean continuum flux. We argue that the data are consistent with the simple model prediction that the size of the broad-line region is proportional to the square root of the ionizing luminosity. Moreover, the apparently linear nature of the correlation between the H-beta response time and the nonstellar optical continuum arises as a consequence of the changing shape of the continuum as it varies, specifically with the optical (5100 A) continuum luminosity proportional to the ultraviolet (1350 A) continuum luminosity to the 0.56 power.Comment: 20 pages plus 4 figures. Accepted for publication in The Astrophysical Journa

Epigenetic «probes» for lung cancer monitoring: LINE-1 methylation pattern in blood- circulating DNA

Malignant cell transformation is accompanied by two processes of DNA methylation changes: promoter hypermethylation of specific genes and hypomethylation of retrotransposons. The composition of circulating DNA (cirDNA) from plasma and cell-surface-bound circulating DNA (csb- cirDNA) was shown earlier to be altered in the blood of cancer patients due to accumulation of tumor- specific aberrantly methylated DNA fragments, which are currently considered valuable cancer markers. The present study compares LINE-1 retrotransposon methylation patterns in plasma cirDNA and csb- cirDNA from 21 untreated lung cancer patients (LC) and 23 healthy donors. Concentrations of methylated LINE-1 region 1 copies (LINE-1met) were assayed by real-time methylation-specific PCR. In order to normalize the LINE-1 methylation level, the LINE-1 region 2 concentration was evaluated, which was independent of the methylation status (LINE-1Ind). The LINE-1met concentration in csb-cirDNA tended to decrease (by a factor of 1.4) in blood from LC patients in comparison to healthy donors (Mann- Whitney test, P=0.16). The LINE-1Ind concentration in csb-cirDNA (methylation-independent) was found to be threefold lower in LC patients and fourfold lower in patients with adenocarcinoma than in healthy donors. That is why, along with the expected decrease in LINE-1met concentration in csb-cirDNA, we recorded an unexpected statistically significant increase of the LINE-1 methylation index determined as (LINE-1met/LINE-1Ind) due to the profound LINE-1Ind decrease. Plasma cirDNA demonstrated no difference in the LINE-1 methylation index (LINE-1met/LINE-1Ind) between LC patients and healthy donors (Mann-Whitney test, P = 0.40). The data obtained agree with our earlier results, which showed that csb-cirDNA was a highly informative material for lung cancer diagnostics