vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2024-14-5-533-546vedomostiregmed-710Research ArticleРЕГУЛИРОВАНИЕ ОБРАЩЕНИЯ ЛЕКАРСТВЕННЫХ СРЕДСТВREGULATION OF MEDICINESКлассификация продуктов клеточной терапии по степени манипулирования клеток и выполняемым функциям: анализ международных регуляторных подходовClassification of Cell Therapy Products by Cell Manipulation Degree and Functions Performed: Analysis of International Regulatory Approacheshttps://orcid.org/0000-0002-6008-0554ВодяковаМ. А.VodyakovaM. A.

Водякова Марина Андреевна - канд. фарм. наук.

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

Marina A. Vodyakova - Cand. Sci. (Pharm.).

8/2 Petrovsky Blvd, Moscow 127051

vodyakova@expmed.ruhttps://orcid.org/0000-0002-2355-0879ПокровскийН. С.PokrovskyN. S.

Покровский Никита Станиславович.

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

Nikita S. Pokrovsky.

8/2 Petrovsky Blvd, Moscow 127051

https://orcid.org/0000-0001-9026-0508СеменоваИ. С.SemenovaI. S.

Семенова Ирина Семеновна - канд. биол. наук.

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

Irina S. Semenova - Cand. Sci. (Biol.).

8/2 Petrovsky Blvd, Moscow 127051

https://orcid.org/0000-0003-4891-973XМеркуловВ. A.MerkulovV. A.

Меркулов Вадим Анатольевич - д-р мед. наук, проф.

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

Vadim A. Merkulov - Dr. Sci. (Med.), Prof.

8/2 Petrovsky Blvd, Moscow 127051

https://orcid.org/0000-0002-9585-3545МельниковаЕ. В.MelnikovaE. V.

Мельникова Екатерина Валерьевна - канд. биол. наук.

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

Ekaterina V. Melnikova - Cand. Sci. (Biol.).

8/2 Petrovsky Blvd, Moscow 127051

Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202403112024145533546Copyright © Водякова М.А., Покровский Н.С., Семенова И.С., Меркулов В.A., Мельникова Е.В., 20242024Водякова М.А., Покровский Н.С., Семенова И.С., Меркулов В.A., Мельникова Е.В.Vodyakova M.A., Pokrovsky N.S., Semenova I.S., Merkulov V.A., Melnikova E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/710ВВЕДЕНИЕ

ВВЕДЕНИЕ. Степень обработки (манипулирования) клеток, входящих в состав клеточных препаратов, и выполняемые ими функции после введения (гомологичное/ негомологичное применение) определяют их отнесение к классу трансплантатов или высокотехнологичных лекарственных препаратов и, соответственно, особенности регулирования их обращения. В законодательстве Евразийского экономического союза (ЕАЭС) и Российской Федерации в настоящее время недостаточно полно разъяснены термины «минимальные манипуляции» и «гомологичное/негомологичное применение», что может служить причиной применения у человека клеточных препаратов с недоказанной безопасностью и эффективностью.

ЦЕЛЬ

ЦЕЛЬ. Сравнение международных и российских подходов к интерпретации терминов «минимальные манипуляции», «гомологичное/негомологичное применение» на примере препаратов стромально-васкулярной фракции (СВФ) с целью классификации препарата и определения пути его регулирования.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Рассмотрены и обобщены регуляторные подходы Российской Федерации, ЕАЭС, США и ЕС в зависимости от классификации клеточных препаратов по степени манипулирования входящих в их состав клеток и выполняемых ими функций после применения. Проведены анализ и сравнение нормативно-правовых актов и подходов рассмотренных стран на примере препаратов на основе СВФ. Показаны общие аспекты толкования терминов «минимальные манипуляции» и «гомологичное/негомологичное применение», продемонстрировано различие в регуляторных подходах разных стран, заключающееся в отнесении ферментативной обработки и селективного отбора клеток к существенным или минимальным манипуляциям.

ВЫВОДЫ

ВЫВОДЫ. Механизм регулирования обращения клеточных препаратов зависит от степени обработки клеток в их составе (минимальное или существенное манипулирование) и от предполагаемого применения (гомологичного или негомологичного). Общим принципом отнесения манипуляций к минимальным, принятым регуляторными организациями США, ЕС, ЕАЭС, Российской Федерации, является сохранение биологических характеристик и физиологической функции продуктов после их проведения; признаком гомологичного применения клеток или тканей является их использование для выполнения присущих им функций в организме. В России перечень манипуляций, отнесенных к минимальным, определен в нормативных актах как для высокотехнологичных лекарственных препаратов, так и для объектов трансплантации. Препараты на основе минимально манипулированных клеток стромально-васкулярной фракции, согласно международным нормам, при негомологичном применении классифицируются как высокотехнологичные лекарственные препараты. Термины «минимальные манипуляции» и «гомологичное/негомологичное применение» недостаточно полно и четко определены в законодательстве ЕАЭС и Российской Федерации, поэтому актуальной является разработка рекомендаций по их разъяснению на конкретных примерах.

INTRODUCTION

INTRODUCTION. The degree of processing (manipulation) of cells included in a cell product and the functions performed after administration (homologous/non-homologous use) determine the classification of the cell product as a transplant or an advanced therapy medicinal product (ATMP) and, hence, the regulatory aspects of the product’s life cycle. Currently, the legislation of the Eurasian Economic Union (EAEU) and the Russian Federation does not sufficiently explain the terms ‘minimal manipulation’ and ‘homologous/non-homologous use’, which may lead to the use of cell products with unproven safety and efficacy in humans.

AIM

AIM. This study aimed to compare Russian and international approaches to the interpretation of the terms ‘minimal manipulation’ and ‘homologous/non-homologous use’ for classifying cell products and determining their regulatory pathways, with stromal vascular fraction (SVF) products used as an example.

DISCUSSION

DISCUSSION. This article reviews and summarises the regulatory approaches of the Russian Federation, the EAEU, the United States (US), and the European Union (EU) that are based on the classification of cell products according to the degree of cell manipulation and the functions performed after administration. The authors have analysed and compared the regulatory acts and approaches of the countries under consideration, with SVF products as a case study. The article highlights general aspects of interpreting the terms ‘minimal manipulation’ and ‘homologous/ non-homologous use’ and demonstrates the difference in regulatory approaches across several countries, which lies in the classification of enzymatic processing and selective collection of cells as substantial or minimal manipulation.

CONCLUSIONS

CONCLUSIONS. The mechanism for regulating cell products depends on the degree of cell manipulation (substantial or minimal) and the intended use (homologous or non-homologous). A common principle adopted by regulatory agencies in the US, EU, EAEU, and Russia is to classify manipulation as minimal if the manipulated cells preserve their biological characteristics and physiological function. A defining characteristic of the homologous use of cells or tissues is their administration to perform their inherent functions in the body. In Russia, the regulatory acts for ATMPs and for transplants list the procedures classified as minimal manipulation. According to international standards, preparations based on minimally manipulated SVF cells are classified as ATMPs when used non-homologously. The lack of comprehensive and clear explanations of the terms ‘minimal manipulation’ and ‘homologous/non-homologous use’ in the legislation of the EAEU and the Russian Federation necessitates the development of relevant guidelines providing specific examples.

стромально-васкулярная фракцияжировая тканьвысокотехнологичный лекарственный препаратправовое регулированиеконтроль качествастепень манипулирования клетокклеточный препаратминимальные манипуляциигомологичное применениенегомологичное применениеstromal vascular fractionfat tissueadvanced therapy medicinal productATMPlegal regulationquality controldegree of cell manipulationcell productminimal manipulationhomologous usenon-homologous useРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 05600026-24-01 на проведение прикладных научных исследований (номер государственного учета НИР 124022200093-9).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. 05600026-24-01 (R&D Registry No. 124022200093-9).ReferencesМельникова ЕВ, Горяев АА, Савкина МВ, Меркулова ОВ, Чапленко АА, Рачинская ОА и др. 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The authors declare that there are no conflicts of interest present.