biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2024-24-3-322-334biopreparat-602Research ArticleРЕГУЛИРОВАНИЕ ОБРАЩЕНИЯ БИОЛОГИЧЕСКИХ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВREGULATION OF BIOLOGICAL MEDICINAL PRODUCTSОсобенности регулирования обращения лекарственных препаратов бактериофагов: международный опыт и перспективы развитияSpecific aspects of bacteriophage regulation: international practices and future developmentshttps://orcid.org/0000-0002-1768-1362ДавыдовД. С.DavydovD. S.

Давыдов Дмитрий Сергеевич, канд. биол. наук

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

Dmitry S. Davydov, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

davydov@expmed.ruhttps://orcid.org/0000-0001-8190-9299ПарфенюкР. Л.ParfenyukR. L.

Парфенюк Римма Леонтьевна, канд. биол. наук

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

Rimma L. Parfenyuk, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

Parfenuk@expmed.ruhttps://orcid.org/0000-0003-2845-1359ДурмановаЗ. В.DurmanovaZ. V.

Дурманова Зоя Владимировна

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

Zoya V. Durmanova

8/2 Petrovsky Blvd, Moscow 127051

durmanova@expmed.ruhttps://orcid.org/0000-0003-0802-4229КазаковР. Е.KazakovR. E.

Казаков Руслан Евгеньевич, канд. биол. наук

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

Ruslan E. Kazakov, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

kazakov@expmed.ruhttps://orcid.org/0000-0003-2132-0962МовсесянцА. А.MovsesyantsA. A.

Мовсесянц Арташес Авакович, д-р мед. наук, проф.

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

Artashes A. Movsesyants, Dr. Sci. (Med.), Prof.

8/2 Petrovsky Blvd, Moscow 127051

movsesyants@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202404102024243Разработка диагностических, лечебных и профилактических препаратов противовирусного действия322334Copyright © Давыдов Д.С., Парфенюк Р.Л., Дурманова З.В., Казаков Р.Е., Мовсесянц А.А., 20242024Давыдов Д.С., Парфенюк Р.Л., Дурманова З.В., Казаков Р.Е., Мовсесянц А.А.Davydov D.S., Parfenyuk R.L., Durmanova Z.V., Kazakov R.E., Movsesyants 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.biopreparations.ru/jour/article/view/602ВВЕДЕНИЕ

ВВЕДЕНИЕ. Увеличение распространенности штаммов возбудителей заболеваний с множественной лекарственной устойчивостью определяет необходимость применения принципиально новых средств борьбы с бактериями, в том числе лекарственных препаратов бактериофагов. Стабильному внедрению фаготерапии мешает отсутствие общепринятых стандартизированных нормативных правовых и методических документов, регламентирующих проведение доклинических и клинических исследований, а также производство препаратов бактериофагов.

ЦЕЛЬ

ЦЕЛЬ. Анализ международного опыта в области организации производства и обращения лекарственных препаратов бактериофагов, а также основных нормативных требований к контролю их качества, эффективности и безопасности.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Разработка препаратов вирулентных бактериофагов в соответствии с существующими требованиями к лекарственным средствам труднореализуема в связи с биологическими характеристиками бактериофагов, большим разнообразием их штаммов, возможными быстрыми изменениями, происходящими как в популяции бактериофагов, так и в популяции возбудителей. В связи с этим целесообразна разработка облегченных подходов к регистрации препаратов фаготерапии и упрощенных методов оценки их эффективности и безопасности. При этом необходима оценка специфических для этой группы препаратов нежелательных явлений, таких как риск развития лизогении и резистентности к бактериофагам, а также возможности переноса генов устойчивости к антибиотикам между штаммами бактерий. Во многих странах мира, в том числе в США, при фармацевтической разработке препаратов бактериофагов используется несколько подходов: концепция «качество через разработку» (Quality by Design); подход, основанный на формировании «мастер-файла на биологическую активную фармацевтическую субстанцию» (Biological Master File), согласно которому подается на одобрение регулирующих органов отдельный пакет документов, охватывающий только часть досье; программа «расширенного доступа» (Expanded Access), открывающая отдельному пациенту возможность применять инновационные препараты без утвержденных протоколов лечения. В России промышленное производство лекарственных препаратов бактериофагов осуществляется в соответствии со стандартами качества, указанными в Государственной фармакопее Российской Федерации.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Подходы к фаготерапии и ее регулированию, принятые в мире и на территории Российской Федерации, в значительной степени отличаются. Представляется целесообразным дополнить существующие национальные рекомендации в сфере анализа эффективности и безопасности лекарственных препаратов бактериофагов, в частности регламентировать обязательность проведения доклинических исследований.

INTRODUCTION

INTRODUCTION. The increasing prevalence of multidrug-resistant strains of pathogens determines the need for fundamentally new antibacterial agents, including bacteriophage preparations. The consistent implementation of phage therapy is hindered by the lack of generally accepted standardised regulatory documents governing the legal and methodological aspects of the production and preclinical and clinical studies of bacteriophage preparations.

AIM

AIM. This study aimed to analyse the international experience with the production and lifecycle management of bacteriophage preparations, as well as the main regulatory requirements for the control of their quality, safety, and efficacy.

DISCUSSION

DISCUSSION. It is difficult to develop virulent bacteriophage preparations in accordance with the existing requirements for other medicinal products because of the biological characteristics of bacteriophages, the wide variety of bacteriophage strains, and the potential for rapid changes both in the bacteriophage population and in the pathogen population. Therefore, it is reasonable to develop streamlined marketing authorisation routes for phage therapies and methods for the assessment of their safety and efficacy. As part of these efforts, it is necessary to assess the adverse events specific to this group of medicinal products, such as the risks of lysogeny, resistance to bacteriophages, and antibiotic resistance gene transfer between bacterial strains. The pharmaceutical development of bacteriophage preparations can be based on several approaches. Many countries worldwide, including the United States, are implementing the concept of Quality by Design, considering approaches based on the Biological Master File, and conducting Expanded Access programmes. The Active Substance Master File procedure allows the submission of a separate document package covering only part of the registration dossier for regulatory approval. Expanded Access programmes provide individual patients with access to innovative medicinal products without approved treatment protocols. In the Russian Federation, the commercial production of bacteriophage medicinal products is conducted in accordance with the quality standards specified in the State Pharmacopoeia of the Russian Federation.

CONCLUSIONS

CONCLUSIONS. There are fundamental differences in the approaches to phage therapy and its regulation around the world and in the Russian Federation. It is reasonable to supplement the current national guidelines for the safety and efficacy evaluation of bacteriophage preparations, in particular, to specify the requirements for conducting preclinical studies.

бактериофагилекарственные препараты бактериофаговфаготерапияперсонализированные препараты бактериофаговпроизводство препаратов бактериофаговобращение лекарственных средствгосударственная регистрация лекарственных средствмножественная лекарственная устойчивостьQuality by Designbacteriophagesbacteriophage preparationsphage therapypersonalised bacteriophage preparationsproduction of bacteriophage preparationsmedicinal product lifecyclemarketing authorisation of medicinesmultidrug resistanceQuality by DesignРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00026-24-01 на проведение прикладных научных исследований (номер государственного учета НИР № 124022200103-5)This study was conducted by the Scientific Centre for Expert Evaluation of Medicinal Products as part of the applied research funded under State Assignment No. 056-00026-24-01 (R&D Registry No. 124022200103-5)ReferencesCooper CJ, Khan Mirzaei M, Nilsson AS. 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The authors declare that there are no conflicts of interest present.