safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2023-11-1-329safetyrisk-329Research ArticleДОКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯPRECLINICAL STUDIESГенотерапевтические препараты: аспекты доклинического изучения безопасностиGene Therapy Medicinal Products: Non-clinical Safety Studieshttps://orcid.org/0000-0003-3089-8395АстаповаО. В.AstapovaO. V.

Астапова Оксана Вадимовна

127051, Москва, Петровский б-р, д. 8, стр. 2

Oksana V. Astapova

127051, Moscow, Petrovsky Blvd, 8/2

astapova@expmed.ruhttps://orcid.org/0000-0003-1462-2911БерчатоваА. А.BerchatovaA. A.

Берчатова Анастасия Александровна

127051, Москва, Петровский б-р, д. 8, стр. 2

Anastasia A. Berchatova

127051, Moscow, Petrovsky Blvd, 8/2

berchatovaaa@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation2023170120231117396Copyright © Астапова О.В., Берчатова А.А., 20232023Астапова О.В., Берчатова А.А.Astapova O.V., Berchatova A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/329

Генотерапевтические лекарственные препараты (ГТЛП) в настоящее время активно разрабатываются в различных странах, в том числе в Российской Федерации. Однако их применение сопряжено с особыми проблемами безопасности, специфичными для этого класса препаратов.Цель работы: определить основные требования к доклинической оценке безопасности и особые риски применения ГТЛП, установить критерии экспертной оценки и выявить возможности оптимизации программы доклинических исследований ГТЛП на основе опыта экспертизы документов и регистрации препаратов этого класса в Российской Федерации и за рубежом.В Российской Федерации, государствах — членах Евразийского экономического союза, Европейском союзе и США создана и продолжает совершенствоваться нормативная база, регулирующая обращение ГТЛП. Свойства ГТЛП обуславливают уникальные проблемы безопасности, такие как инсерционный мутагенез, нерегулируемая экспрессия трансгена, долговременная персистенция и нецелевое распространение, вертикальный перенос генов, а также риск для окружающей среды. В связи с этим в рамках комплексной программы доклинического изучения безопасности ГТЛП может потребоваться проведение дополнительных специальных исследований наряду со стандартными. В обзоре рассмотрены основные подходы к дизайну исследований и оценке полученных результатов изучения безопасности неклеточных ГТЛП. Определены проблемные моменты дизайна исследований и возможности его модификации, условия и ограничения экстраполяции доклинических данных и прогнозируемости профиля клинической безопасности препаратов. Ввиду того что нормативная база, регулирующая доклинические исследования ГТЛП, постоянно обновляется и актуализируется, при разработке программы доклинической оценки безопасности ГТЛП следует учитывать весь накопленный опыт и опираться как на отечественные, так и на зарубежные руководства и рекомендации в этой области.

Currently, gene therapy medicinal products (GTMPs) are actively developed in many countries, including the Russian Federation. However, the use of GTMPs raises class-specific safety concerns.The aim of the study was to determine the main requirements for non-clinical safety testing of GTMPs, to identify risks associated with these medicinal products, to establish criteria for expert assessments, and to find optimisation opportunities for GTMP non-clinical safety programmes, using Russian and international experience in the assessment of submissions and the registration of medicinal products of this class.The Russian Federation, the Eurasian Economic Union, the European Union, and the United States have created regulatory frameworks governing the lifecycle of GTMPs and continue improving these frameworks. The properties of GTMPs may create unique safety issues, such as insertional mutagenesis, unregulated transgene expression, long-term persistence and off-target spread, vertical germline transmission, and environmental risks. To account for these issues, a comprehensive non-clinical safety programme for GTMPs may require additional special studies along with the standard ones. This review focuses on the main approaches to designing non-cellular GTMP safety studies and evaluating the obtained results. The authors identified improvement opportunities for and problematic aspects of study design, as well as conditions for and limitations of non-clinical data extrapolation and clinical safety profile prediction. The continuous improvement and updating of the regulatory frameworks governing non-clinical studies of GTMPs mean that developers of non-clinical safety programmes for GTMPs should use all their experience, as well as relevant national and international guidelines and recommendations.

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The authors declare that there are no conflicts of interest present.