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

Regulation for the Translation of Gene and Cell Therapy into Medical Practice in East Asian Countries

SCIENTIFIC RELEVANCE. Currently, the Russian Federation lacks a comprehensive regulatory framework for the use of gene and cell therapy (GCT) products. There is no standard for conducting clinical trials for purposes other than marketing authorisation in Russia. In contrast, international practice shows that, in addition to marketing authorisation, including approval based on incomplete data with post-approval commitments, there are regulatory mechanisms for the use of unregistered GCT products, such as hospital exemptions, expanded access, or compassionate use in the European Union and the USA. Relatively recently, this framework has been reformed in East Asian countries.AIM. This study aimed to analyse the regulatory mechanisms for translating GCT products into medical practice in East Asian countries and to assess the possibility of transferring elements of international experience to Russian practice.DISCUSSION. East Asian countries have adopted legislation on requirements for the manufacturing and medicinal use of GCT products. These requirements include having a mandatory license for production in accordance with Good Manufacturing Practice, consideration of the rationale for the use of GCT products by regulatory authorities or special committees, risk classification of investigational GCT products, approved registries of medical institutions authorised to use GCT products, and necessary monitoring and control of patients after GCT administration. Only cellbased innovative medicines, including genetically modified cells, are used within the framework of medical technologies (Japan, China, and Taiwan) or services (Republic of Korea), and in vivo gene therapy products can be used only in investigator-initiated clinical trials.CONCLUSIONS. The East Asian experience in translating GСT products into medical practice would be extremely useful for the Russian Federation, especially in terms of GСT use for specific indications based on accumulated clinical experience. The review suggests that it would be appropriate to establish legal provisions for investigator-initiated clinical research in Russian national legislation

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

Advanced Therapy Medicines Based on Oncolytic Viruses (Part II: Development and Authorisation of IMLYGIC®)

The only oncolytic virus-based product authorised in the US and EU—IMLYGIC®, a genetically modified herpes simplex virus type 1 (by BioVex Inc., a subsidiary of Amgen, Inc.)—was developed and approved for clinical use as monotherapy for recurrent unresectable melanoma. The aim of the study was to analyse materials on IMLYGIC® development and authorisation in order to be able to use the data on specific aspects of preclinical and clinical trials of oncolytic virus-based products in the development of regulatory framework for Russia and the EAEU. The publicly available preclinical and clinical trial results demonstrate a decrease in the size of both tumours being injected and remote tumours/skin lesions, which supports the local and systemic effects of IMLYGIC® due to the lysis effect of the virus on the tumour cells. The clinical trials of IMLYGIC® were the first to use the durable response rate, and not the overall survival, as the primary endpoint of the efficacy of the anticancer drug. Benefits of IMLYGIC® therapy were observed across all the secondary endpoints, except overall survival. Significant efficacy of the drug therapy was demonstrated only in patients without visceral lesions, which resulted in limitations of indications for use. There have been no serious or severe adverse effects associated with IMLYGIC®. If symptoms of viral infection develop, they can be neutralized thanks to the product’s sensitivity to acyclovir. At present, advanced therapy medicinal products derived from an oncolytic virus may be authorised in Russia for clinical use as monotherapy or combination therapy, according to the EAEU regulations

Current trends and risks associated with the use of therapies based on genome editing

Scientific relevance. To date, multiple approaches to genome editing have been developed based on different genome-editing systems (GESs) and genome modifications that result in single- or double-strand DNA breaks, either in vivo or ex vivo, followed by homologous recombination or non-homologous end joining to restore the sequence. However, the use of GESs is associated with a number of potential risks arising from the complex biology of such medicinal products and the fundamental role of their target, i.e. the DNA molecule.Aim. This study analysed the most relevant trends and risks associated with medicinal products based on genome editing, the ways taken to overcome these risks, and the research methods used to identify and control the development of undesirable effects.According to the literature, the adverse effects of GESs may arise both from the methods used to deliver GES components into the cell and from the functional activity of the GES itself, which includes insufficient on-target or undesirable off-target effects. This review indicates the main risks associated with the use of GESs. Preferable strategies to mitigate the risks of using GESs include repairing DNA breaks by homologous recombination, selecting GESs and related endonucleases that have greater specificity and restriction accuracy, increasing guide RNA specificity (for CRISPR/Cas), correcting the activity of the system regulating the cell cycle and apoptosis in a controlled manner, regulating the duration of expression and persistence of GES components in cells, etc.Conclusions. The requirement to include quality, efficacy, and safety data when submitting registration dossiers for advanced therapy medicinal products prompts the discussion of the main risks associated with such products

Advanced Therapy Medicines Based on Oncolytic Viruses (Part I: Development and Authorisation of Products in China)

One of the promising areas in the development of innovative products for the treatment of cancer is the use of oncolytic (native or genetically modified) viruses (OLVs) for selective targeting of tumour cells and their destruction, especially as part of combination therapy. At present, there are three OLV-based products approved for medical use (two in China and one in the USА and EU). The aim of the study was to analyse data on specific aspects of OLV-based products’ development, preclinical and clinical research, and authorisation process in China. The authors analysed data freely available on the manufacturers’ websites, in public reports and documents of the Chinese regulatory authorities, in international clinical trial registries, and scientific publications. The products Gendicine® (SiBiono GeneTech Co., Ltd.) and Oncorine® (Shanghai Sunway Biotech Co., Ltd.) were originally developed and approved in China for clinical use as part of combination therapy. The analysis demonstrated long product development periods (Gendicine had been studied for 14 years before the start of the authorisation procedures), complex preclinical trial designs, and potential use of the products for several medical conditions with different tumour localisation. The identified specific aspects of OVL-based products’ development and authorisation in China could be taken into account in the regulatory practice of the Russian Federation

Лікувально-діагностична тактика при рідинно-кістозних утвореннях підшлункової залози

Мета. Розроблення лікувально–діагностичної тактики при рідинно–кістозних утвореннях підшлункової залози. Матеріали і методи. Дослідження проведено щодо 48 хворих з гострим деструктивним панкреатитом, ускладненим рідинно–кістозними утвореннями. З діагностичною метою виконували пункцію під контролем ультразвукового дослі- дження з подальшим мікробіологічним та морфологічним дослідженням отриманого аспірату. Результати. Вибір методики залежить від ефективності втручання, яка ґрунтується на вивченні ультразвукової карти- ни досліджуваної зони до та під час втручання, а також у ході динамічного дослідження після операції. Висновки. Використовуючи в комплексній діагностиці морфологічний метод дослідження, можливо в ранні строки диференціювати рідинно–кістозні утворення як ускладнення гострого деструктивного панкреатиту та визначити лі- кувальну тактику

Optical control of spin coherence in singly charged (In,Ga)As/GaAs quantum dots

Electron spin coherence has been generated optically in n-type modulation doped (In,Ga)As/GaAs quantum dots (QDs) which contain on average a single electron per dot. The coherence arises from resonant excitation of the QDs by circularly-polarized laser pulses, creating a coherent superposition of an electron and a trion state. Time dependent Faraday rotation is used to probe the spin precession of the optically oriented electrons about a transverse magnetic field. Spin coherence generation can be controlled by pulse intensity, being most efficient for (2n+1)pi-pulses.Comment: 5 pages, 4 figure

Manipulation of the Spin Memory of Electrons in n-GaAs

We report on the optical manipulation of the electron spin relaxation time in a GaAs based heterostructure. Experimental and theoretical study shows that the average electron spin relaxes through hyperfine interaction with the lattice nuclei, and that the rate can be controlled by the electron-electron interactions. This time has been changed from 300 ns down to 5 ns by variation of the laser frequency. This modification originates in the optically induced depletion of n-GaAs layer

DEVELOPMENT OF SrFe12O19 AND BaFe12O19 OXYGEN ACCUMULATORS FOR CHEMICAL CYCLING TECHNOLOGY

The study evaluates (Sr,Ba)Fe12O19 oxides for their potential use in chemical cycling technology. SrFe12O19 has a higher oxygen capacity and remains stable after 9 cycles, making it a promising candidate for an oxygen accumulator. BaFe12O19 degrades over time, indicating limitations in its use.Работа выполнена при поддержке Российского Научного Фонда, проект № 22-79-00229