pmjТихоокеанский медицинский журналPacific Medical Journal1609-1175TGMU10.34215/1609-1175-2020-3-11-18pmj-484Research ArticleОБЗОРЫREVIEWSПринципы клинических исследований препаратов фактора свертывания крови IXPrinciples for clinical trials of coagulation factor IX productshttps://orcid.org/0000-0002-9377-1378АвдееваЖ. И.AvdeevaZh. I.

д-р мед. наук, профессор, главный эксперт центра экспертизы и контроля,

121002, г. Москва, ул. Сивцев Вражек, 41

MD, PhD, professor, chief expert of the Center for Examination and Control, 

41 Sivtsev Vrazhek St., Moscow, 121002

avd-cytok@yandex.ruhttps://orcid.org/0000-0001-6624-2692СолдатовА. А.SoldatovA. A.

д-р мед. наук, главный эксперт управления экспертизы аллергенов, цитокинов и других иммуномодуляторов,

121002, г. Москва, ул. Сивцев Вражек, 41

MD, PhD, chief expert of the Office of Expertise Allergens, Cytokines and Other Immunomodulators,

41 Sivtsev Vrazhek St., Moscow, 121002

soldatov@expmed.ruhttps://orcid.org/0000-0001-6472-6386БондаревВ. П.BondarevV. P.

д-р мед. наук, профессор, директор Центра экспертизы и контроля медицинских иммунобиологических препаратов,

121002, г. Москва, ул. Сивцев Вражек, 41

MD, PhD, professor, director of the Centre of Expertise of the Medical Immunobiological Preparations Quality,

41 Sivtsev Vrazhek St., Moscow, 121002

bondarev@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

д-р мед. наук, профессор, заместитель генерального директора по экспертизе лекарственных средств,

121002, г. Москва, ул. Сивцев Вражек, 41

MD, PhD, professor, deputy director general for the expertise of drugs, 

41 Sivtsev Vrazhek St., Moscow, 121002

merkulov@expmed.ruНаучный центр экспертизы средств медицинского примененияРоссияScientific Centre for Expert Evaluation of Medicinal Products, MoscowRussian FederationНаучный центр экспертизы средств медицинского примененияРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202028092020031118Copyright © Авдеева Ж.И., Солдатов А.А., Бондарев В.П., Меркулов В.А., 20202020Авдеева Ж.И., Солдатов А.А., Бондарев В.П., Меркулов В.А.Avdeeva Z.I., Soldatov A.A., Bondarev V.P., Merkulov V.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.tmj-vgmu.ru/jour/article/view/484

Обзор материалов, касающихся научных принципов, лежащих в  основе клинических исследований лекарственных препаратов фактора свертывания крови IX, полученных с использованием технологии рекомбинантных ДНК или из плазмы крови доноров. Наследственный дефицит функционально активного фактора свертывания крови IX или низ‑ кий уровень его синтеза приводят к развитию гемофилии В. Больным гемофилией требуется постоянная заместитель‑ ная терапия препаратами фактора IX. Достижения в области генно-инженерных технологий, а также совершенствова‑ ние процесса производства биологических препаратов позволяет разрабатывать современные высокоэффективные лекарственные средства, которые успешно применяются для лечения пациентов с  гемофилией. Регистрация вновь разработанных препаратов и  лекарственных средств, произведенных по измененной технологии, предусматривает проведение клинических исследований. Принципы этих исследований регламентируются положениями регулярно обновляющихся нормативных документов. Соблюдение отечественных и международных рекомендаций, определяющих условия клинических испытаний лекарственных средств, позволяет гарантировать их безопасность и  способствует разработке препаратов, обеспечивающих качественное лечение пациентов с гемофилией.

Review of materials related to scientific principles underlying clinical trials of coagulation factor IX medications obtained using recombinant DNA technique or from donors’ blood plasma. Inherited deficiency of functional active coagulation factor IX or a low level of its synthesis lead to the development of hemophilia B. Patients with hemophilia require a continuous replacement therapy with factor IX medications. Achievements in the area of genetically engineering technologies as well as improvement of production process of biological products allow developing modern highly efficient medications which are successfully used to treat patients with hemophilia. Registration of newly developed medications and medications produced according to the modified technology requires clinical trials. Principles of these trials are regulated by the clauses of regularly updated regulatory documents. Compliance with national and international guidelines determining the conditions for clini‑ cal trials of medications allows us to guarantee their safety and promotes the development of medications efficient to treat patients with hemophilia.

гемофилиядетизаместительная терапияфактор IXклинические исследованияhemophiliachildrenreplacement therapyfactor IXclinical trialsРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00003-20-00 на проведение прикладных научных исследований (номер государственного учета НИР AAAA-A18-118021590046-9).ReferencesGuideline on the clinical investigation of recombinant and human plasma-derived factor IX products EMA/CHMP/BPWP/144552/2009. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109691.pdf (Accessed July 6, 2018).Guideline on the clinical investigation of recombinant and human plasma-derived factor IX products EMA/CHMP/BPWP/144552/2009. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109691.pdf (Accessed July 6, 2018).Guideline on clinical investigation of recombinant and human plasma-derived factor IX products: Committee for medicinal products for human use. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187413. pdf (Accessed July 6, 2018).Guideline on clinical investigation of recombinant and human plasma-derived factor IX products: Committee for medicinal products for human use. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187413. pdf (Accessed July 6, 2018).Руководство по проведению клинических исследований лекарственных средств (иммунобиологические лекарственные препараты). М.: Гриф и К, 2013;2:212.Guidance on the conduct of clinical trials of drugs (immunobiological drugs). Moscow: Grif and K; 2013;2:212 (in Russ).Зозуля Н.И., Свирин П.В. Диагностика и лечение гемофилии. Национальные клинические рекомендации. Под ред. акад. В.Г. Савченко. М.: Национальное гематологическое общество, 2014:34.Zozulya NI, Svirin PV. Diagnosis and treatment of hemophilia. National clinical guidelines. Moscow: National Hematological Society; 2014:34 (in Russ).Руководство по гематологии. Под ред. А.И. Воробьева. 3-е изд. М.: Ньюдиамед, 2005;3:280.Vorobyev AI, ed. Guideline for gematology. Moscow: Newdiamed; 2005;3:280 (in Russ).Руководство по лечению гемофилии. Публикация Всемирной федерации гемофилии, 2008. URL: https://www.wfh.org/en/page.aspx.pid=492 (Accessed July 6, 2018).Hemophilia Treatment Guide. World Federation of Hemophilia; 2008 (In Russ). URL: https://www.wfh.org/en/page.aspx.pid=492 (Accessed July 6, 2018).Ogston D, Bennett В, eds. Hemostasis. London: Willey; 1977.Ogston D, Bennett В, eds. Hemostasis. London: Willey; 1977.ICH Q5A (R1) guideline. Quality of biotechnological products: Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin. Geneva, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1999. URL: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5A_R1/Step4/Q5A_R1__Guideline.pdf (Accessed July 6, 2018).ICH Q5A (R1) guideline. Quality of biotechnological products: Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin. Geneva, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1999. URL: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5A_R1/Step4/Q5A_R1__Guideline.pdf (Accessed July 6, 2018).Guidance on virus validation studies. The design, contribution and interpretation of studies validating the inactivation and removal of viruses. London; 2009. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003795.pdf (Accessed July 6, 2018).Guidance on virus validation studies. The design, contribution and interpretation of studies validating the inactivation and removal of viruses. London; 2009. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003795.pdf (Accessed July 6, 2018).Guideline on virus safety evaluation of biotechnological investigational medicinal products. London; 2008. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003795.pdf (Accessed July 6, 2018).Guideline on virus safety evaluation of biotechnological investigational medicinal products. London; 2008. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003795.pdf (Accessed July 6, 2018).Правила проведения исследований биологических лекарственных средств Евразийского экономического союза. Решение Совета Евразийской экономической комиссии № 89 от 03.11.2016. М., 2016. Глава 2. URL: https://www.garant.ru/products/ipo/prime/doc/71446406 (Accessed July 6, 2018).Guideline of research of biological medicines of the Eurasian Economic Union. The decision of the Council of the Eurasian Economic Commission No. 89 (03 Nov 2016). Moscow; 2016. Chapter 2 (In Russ). URL: https://www.garant.ru/products/ipo/prime/doc/71446406 (Accessed July 6, 2018).Орлова Н.А., Ковнир С.В., Воробьев И.И., Габибов A.Г. Фактор свертывания крови IX для терапии гемофилии В. Acta Naturae. 2012;4(2):62–75.Orlova NA, Kovnir SV, Vorobev II, Gabibov AG. The blood coagulation factor IX for treatment of hemophilia B. Russian Journal Acta Naturae. 2012;4(2): 62–75 (In Russ).Солдатов А.А., Авдеева Ж.И., Мосягин В.Д., Олефир Ю.В., Бондарев В.П. Основные направления по разработке и модификации препаратов для лечения гемофилии. Гематология и трансфузиология. 2016;61(4):208–15.Soldatov AA, Avdeeva ZhI, Mosyagin VD, Olefir YuV, Bondarev VP. The main directions for the development and modification of drugs for the treatment of hemophilia. Hematology and Transfusiology. 2016;61(4):208–15 (In Russ).ICH E6 guideline. Guideline for good clinical practice. Geneva, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1996. URL: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf (Accessed July 6, 2018).ICH E6 guideline. Guideline for good clinical practice. Geneva, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1996. URL: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf (Accessed July 6, 2018).ICH E8 Note for guidance on general considerations for clinical trials (CPMP/ICH/291/95). URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002877.pdf (Accessed July 6, 2018).ICH E8 Note for guidance on general considerations for clinical trials (CPMP/ICH/291/95). URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002877.pdf (Accessed July 6, 2018).Guidelines for good clinical practice (GCP) for trials on pharmaceutical product. Annex 3 in WHO Expert Committee on Selection and Use of Essential Medicines. 6th report. Geneva, WHO; 1995. URL: http://apps.who.int/medicinedocs/pdf/whozip13e/whozip13e.pdf (Accessed July 6, 2018).Guidelines for good clinical practice (GCP) for trials on pharmaceutical product. Annex 3 in WHO Expert Committee on Selection and Use of Essential Medicines. 6th report. Geneva, WHO; 1995. URL: http://apps.who.int/medicinedocs/pdf/whozip13e/whozip13e.pdf (Accessed July 6, 2018).Руководство по экспертизе лекарственных средств. М.: Гриф и К, 2013;1:328.Guideline for the examination of drugs. Moscow: Grief and K; 2013;1:328 (in Russ).Руководство по проведению доклинических исследований лекарственных средств. М.: Гриф и К, 2013;1:944.Guidance on the conduct of clinical trials of drugs. Moscow: Grief and K; 2013;1:944 (in Russ).Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins (CHMP/EWP/89249/2004). URL: http://www.ema.europa.eu/docs/en_GB/documentlibrary/Scientific_guideline/2009/09/WC500003029.pdf (Accessed July 6, 2018).Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins (CHMP/EWP/89249/2004). URL: http://www.ema.europa.eu/docs/en_GB/documentlibrary/Scientific_guideline/2009/09/WC500003029.pdf (Accessed July 6, 2018).Bond M, Jankowski M, Patel H, Karnik S, Strang A, Xu B, et al. Biochemical characterization of recombinant factor IX. Semin Hematol. 1998;35(S2):11–7.Bond M, Jankowski M, Patel H, Karnik S, Strang A, Xu B, et al. Biochemical characterization of recombinant factor IX. Semin Hematol. 1998;35(S2):11–7.Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: A systematic review. Haemophilia. 2003;9(S4):418–35.Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: A systematic review. Haemophilia. 2003;9(S4):418–35.DiMichele D. Inhibitor development in hemophilia B: An orphan disease in need of attention. Br J Haematol. 2007;138(3):303–15.DiMichele D. Inhibitor development in hemophilia B: An orphan disease in need of attention. Br J Haematol. 2007;138(3):303–15.Agostini D, Rosset C, Botton MR, Kappel DB, Vieira IA, Gorziza RP, et al. Immune system polymorphisms and factor VIII inhibitor formation in Brazilian haemophilia: A severe patients. Haemophilia. 2012;18(S6):416–28.Agostini D, Rosset C, Botton MR, Kappel DB, Vieira IA, Gorziza RP, et al. Immune system polymorphisms and factor VIII inhibitor formation in Brazilian haemophilia: A severe patients. Haemophilia. 2012;18(S6):416–28.ICH E11 guideline. Clinical investigation of medicinal products in the paediatric population. Geneva, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2000. URL: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4/E11_Guideline.pdf (Accessed July 6, 2018).ICH E11 guideline. Clinical investigation of medicinal products in the paediatric population. Geneva, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2000. URL: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4/E11_Guideline.pdf (Accessed July 6, 2018).Negrier C, Knobe K, Tiede A, Giangrande P, Moss J. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: A first human dose trial in patients with hemophilia B. Blood. 2011;118(10):2695–701.Negrier C, Knobe K, Tiede A, Giangrande P, Moss J. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: A first human dose trial in patients with hemophilia B. Blood. 2011;118(10):2695–701.Руководство по экспертизе лекарственных средств. Под ред. А.Н. Миронова. Т. 3. М.: Полиграф-плюс, 2014.Mironov AN, ed. Guideline for the examination of drugs. Moscow: Poligraf-Plus; 2014;3 (In Russ).ICH Q5E Note for Guidance on Biotechnological/Biological Products Subject to Changes in their Manufacturing Process. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002805.pdf (Accessed July 6, 2018).ICH Q5E Note for Guidance on Biotechnological/Biological Products Subject to Changes in their Manufacturing Process. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002805.pdf (Accessed July 6, 2018).Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process – nonclinical and clinical issues. (EMEA/CHMP/BMWP/101695/2006). London: European Medicines Agency; 2007. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003935.pdf (Accessed July 6, 2018).Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process – nonclinical and clinical issues. (EMEA/CHMP/BMWP/101695/2006). London: European Medicines Agency; 2007. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003935.pdf (Accessed July 6, 2018).Авдеева Ж.И., Волкова Р.А., Алпатова Н.А., Солдатов А.А., Медуницын Н.В., Меркулов В.А. Методические приемы и принципы оценки сопоставимости биотехнологических продуктов, полученных до и после внесения изменений в процесс производства. БИОпрепараты. Профилактика, диагностика, лечение. 2013;46(2):18–21.Avdeeva ZhI, Volkova RA, Alpatova NA, Soldatov AA, Medunitsyn NV, Merkulov VA. Methodology and principles for comparability assessment of biopharmaceuticals obtained before and after modifications in the manufacturing process. Russian Journal of BIOpreparations. Prevention, Diagnosis, Treatment. 2013;46(2):18–21 (In Russ).

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