biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Productsbiopreparat-67Research ArticleОБЗОРЫREVIEWSПервые биоподобные лекарственные препараты моноклональных антителFirst available biosimilar monoclonal antibodiesАвдееваЖ. И.AvdeevaZh. I.

Главный эксперт управления экспертизы аллергенов, цитокинов и других иммуномодуляторов Центра экспертизы и контроля МИБП, д-р мед. наук, профессор

Chief expert of Office of expertise allergens, cytokines and other immunomodulators of Center for examination and control of medical immunobiological preparations. Doctor of Medical Sciences, professor

Avd-cytok@yandex.ruСолдатовА. А.SoldatovA. A.

Главный эксперт управления экспертизы аллергенов, цитокинов и других иммуномодуляторов Центра экспертизы и контроля МИБП, д-р мед. наук

Chief expert of Office of expertise allergens, cytokines and other immunomodulators of Center for examination and control of medical immunobiological preparations. Doctor of Medical Sciences

noemail@neicon.ruАлпатоваН. А.AlpatovaN. A.

Главный эксперт лаборатории иммунологии Испытательного центра экспертизы качества МИБП, канд. биол. наук

Chief expert of Laboratory of immunology. Candidate of Biological Sciences

noemail@neicon.ruБондаревВ. П.BondarevV. P.

Директор Центра экспертизы и контроля МИБП, д-р мед. наук, профессор

Director of Center for examination and control of medical immunobiological preparations. Doctor of Medical Sciences, professor, academician of the Russian Academy of Sciences

noemail@neicon.ruОлефирЮ. В.OlefirYu. V.

Генеральный директор, д-р. мед. наук

Director Heneral. Doctor of Medical Sciences

noemail@neicon.ruМеркуловВ. А.MerkulovV. A.

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

Deputy Director Heneral for expertise of drugs. Doctor of Medical Sciences, professor

noemail@neicon.ruМосягинВ. Д.MosyaginV. D.

Начальник управления экспертизы аллергенов, цитокинов и других иммуномодуляторов Центра экспертизы и контроля МИБП, д-р мед. наук, профессор

Head of Office of expertise allergens, cytokines and other immunomodulators of Center for examination and control of medical immunobiological preparations. Doctor of Medical Sciences, professor

noemail@neicon.ruМедуницынН. В.MedunitsynN. V.

Руководитель научного направления, д-р мед. наук, профессор, академик РАН

Head of the scientific direction. Doctor of Medical Sciences, professor, academician of the Russian Academy of Sciences

noemail@neicon.ruНаучный центр экспертизы средств медицинского примененияРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation201620022018164208218Copyright © Авдеева Ж.И., Солдатов А.А., Алпатова Н.А., Бондарев В.П., Олефир Ю.В., Меркулов В.А., Мосягин В.Д., Медуницын Н.В., 20182018Авдеева Ж.И., Солдатов А.А., Алпатова Н.А., Бондарев В.П., Олефир Ю.В., Меркулов В.А., Мосягин В.Д., Медуницын Н.В.Avdeeva Z.I., Soldatov A.A., Alpatova N.A., Bondarev V.P., Olefir Y.V., Merkulov V.A., Mosyagin V.D., Medunitsyn N.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.biopreparations.ru/jour/article/view/67

Обзор посвящен вопросам, связанным с особенностями разработки первых биоподобных/биоаналоговых («biosimilars») лекарственных препаратов на основе моноклональных антител. В июне 2013 года Комитет по лекарственным препаратам для медицинского применения (CHMP) Европейского медицинского агентства по лекарственным средствам (ЕМА) рекомендовал для лицензирования препараты Remsima и Inflectra как биоподобные оригинальному препарату Remicade®/Ремикейд® (инфликсимаб). В обзоре приведены общие принципы разработки указанных биоподобных/биоаналоговых биотехнологических препаратов. Отражены особенности проведения исследований по оценке качества, включающих характеристику физико-химических свойств, специфической биологической активности, а также сравнительных доклинических и клинических исследований, подтверждающих подобие разработанного и оригинального (референтного) препаратов. Представлены материалы, отражающие анализ полученных результатов сравнительных исследований, с целью оценки клинической значимости выявленных различий на этапе оценки качества. Приведены данные, обосновывающие возможность экстраполяции результатов, полученных при проведении клинических исследований, по одним показаниям на другие показания, утвержденные для оригинального препарата.

The review deals with the issues related to the special aspects of the development of the first available similar biopharmaceuticals/biological analogues («biosimilars») based on monoclonal antibodies. In June 2013 the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) approved for licensing Remsima and Inflectra which are biosimilars of the brand-name product Remicade® (infliximab). The review describes the general principles of the development of the mentioned biosimilars. It highlights the features of the quality assessment studies, including characterization of the physical and chemical properties, specific biological activity, as well as comparative preclinical and clinical trials confirming the similarity of the candidate and the brand-name (reference) product. The review provides with the analysis of the results of comparative studies to assess the clinical relevance of the differences detected at the stage of quality assessment. The data substantiating the possibility of extrapolating the results obtained in clinical trials, against the approved standards for the brand-name product is provided.

биоподобные/биоаналоговые («biosimilars») препаратылекарственные препараты моноклональных антителоценка качествадоклинические исследованияклинические исследованияbiosimilar productsmonoclonal antibody productsquality assessmentpreclinical trialsclinical trialsReferencesElliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993; 36(12): 1681-90.Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993; 36(12): 1681–90.Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Ann Rev Immunol. 1996; 14: 397-440.Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Ann Rev Immunol. 1996; 14: 397–440.Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis J, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998; 41(9): 1552-63.Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis J, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998; 41(9): 1552–63.Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM. RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxford) 2006. 45: 1068-76.Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM. RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxford) 2006. 45: 1068–76.Guideline on development, production, characterization and specifications for monoclonal antibodies and related products. London. European Medicines Agency. 2008.Guideline on development, production, characterization and specifications for monoclonal antibodies and related products. London. European Medicines Agency. 2008.Guidelines for assuring the quality of monoclonal antibodies for use in humans. WHO Expert Committee on Biological Standardization. Forty-second report. Geneva, World Health Organization, 1991 (WHO Technical Report Series, No. 822).Guidelines for assuring the quality of monoclonal antibodies for use in humans. WHO Expert Committee on Biological Standardization. Forty-second report. Geneva, World Health Organization, 1991 (WHO Technical Report Series, No. 822).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 Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.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 Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999.Note for guidance on virus validation studies: The design, contribution and interpretation of studies validating the inactivation and removal of viruses (CPMP/BWP/268/95); London. 14 February 1996.Note for guidance on virus validation studies: The design, contribution and interpretation of studies validating the inactivation and removal of viruses (CPMP/BWP/268/95); London. 14 February 1996.Guidance on virus validation studies. The design, contribution and interpretation of studies validating the inactivation and removal of viruses. (EMEA/CHMP/BWP/398498/2005); London. February 2009.Guidance on Virus validation studies. The design, contribution and interpretation of studies validating the inactivation and removal of viruses (EMEA/CHMP/BWP/398498/2005); London. February 2009.ICH Q2A guideline. Validation of Analytical Procedures. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1994.ICH Q2A guideline. Validation of Analytical Procedures. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1994.ICH Q2B guideline. Validation of Analytical Procedures: Methodology. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.ICH Q2B guideline. Validation of Analytical Procedures: Methodology. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996.ICH Q6B guideline. Note For Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (CPMP/ICH/365/96).ICH Q6B guideline. Note For Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (CPMP/ICH/365/96).Assessment report. Remsima (EMA/CHMP/589317/2013). 27 June 2013. Committee for Medicinal Products for Human Use (CHMP).Assessment report. Remsima. (EMA/CHMP/589317/2013). 27 June 2013. Committee for Medicinal Products for Human Use (CHMP).Assessment report. Inflectra (EMA/CHMP/589422/2013). 27 June 2013. Committee for Medicinal Products for Human Use (CHMP).Assessment report. Inflectra. (EMA/CHMP/589422/2013). 27 June 2013. Committee for Medicinal Products for Human Use (CHMP).Guideline on similar biological medicinal products (EMA/CHMP/ 0437/2004). London. 2005.Guideline on similar biological medicinal products (ÅÌÀ/CHMP/ 0437/2004). London. 2005.Guideline on similar biological medicinal products (revision 1) (EMA/CHMP/0437/2004). London. 2014. Effective date: 30 April 2015.Guideline on similar biological medicinal products (revision 1) (ÅÌÀ/CHMP/0437/2004). London. 2014. Effective date: 30 April 2015.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (EMEA/CHMP/BMWP/49348/2005). London. 2006.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (EMEA/CHMP/BMWP/49348/2005). London. 2006.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1) (EMEA/CHMP/BWP/247713/2012). London. 22 May 2014. Effective date: 1 December 2014.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1) (EMEA/CHMP/BWP/247713/2012). London. 22 May 2014. Effective date: 1 Deсember 2014.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues (revision 1). (EMEA/CHMP/BMWP/42832/2005). London. January 2015. Effective date: 1 July 2015.Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues (revision 1) (EMEA/CHMP/BMWP/42832/2005). London. January 2015. Effective date: 1 July 2015.Guidelines on evaluation of similar biotherapeutic products (SBPs). WHO Expert Committee on Biological Standardization. Geneva. 19 to 23 October. 2009.Guidelines on evaluation of similar biotherapeutic products (SBPs). WHO Expert Committee on Biological Standardization. Geneva. 19 to 23 October. 2009.Guidelines on evaluation of similar biotherapeutic products (SBPs). Annex 2 in: WHO Expert Committee on Biological Standardization. Sixtieth report. Geneva, WHO Technical Report Series, No. 977. 2013.Guidelines on evaluation of similar biotherapeutic products (SBPs). Annex 2 in: WHO Expert Committee on Biological Standardization. Sixtieth report. Geneva, WHO Technical Report Series, No. 977. 2013.WHO/KFDA Joint workshop on implementing WHO guidelines on evaluating smilar biotherapeutic products. Meeting Report. Seoul, Republic of Korea 24 - 26 August. 2010 (Accepted 1 August 2011).WHO/KFDA Joint workshop on implementing WHO guidelines on evaluating smilar biotherapeutic products. Meeting Report. Seoul, Republic of Korea 24 – 26 August. 2010 (Accepted 1 August 2011).Guidance for industry. Quality consideration in demonstrating biosimilarity of a therapeutic protein product to a reference product. U. S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER) April 2015.Guidance for industry. Quality consideration in demonstrating biosimilarity of a therapeutic protein product to a reference product. U. S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER) April 2015.Руководство по экспертизе лекарственных средств. Том I. М.: Гриф и К. 2013; с. 289-303.Guideline for the examination of drugs. v. I. Moscow: Grief and K. 2013; p. 289–303 (in Russian).Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010). London. 2012.Guideline on similar biological medicinal products containing monoclonal antibodies — non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010). London. 2012.Руководство по экспертизе лекарственных средств. Том IV. М.: ПОЛИГРАФ-ПЛЮС. 2014; С. 31-53.Guideline for the examination of drugs. v. IV. Moscow: POLIGRAF-PLYuS. 2014; p. 31–53 (in Russian).European Pharmacopoeia 6.0. Monoclonal antibodies for human use. 01/2008:2031.European Pharmacopoeia 6.0. Monoclonal antibodies for human use. 01/2008:2031.ICH Q5C guideline. Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products. International Conference on Harmonization. of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1995.ICH Q5C guideline. Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products. International Conference on Harmonization. of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1995.Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006). London, European Medicines Agency. London, January, 2007.Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006). London, European Medicines Agency. London, January, 2007.Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. (EMA/CHMP/BMWP/ 86289/2010). London, European Medicines Agency. 2012.Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use (EMA/CHMP/BMWP/86289/ 2010). London, European Medicines Agency. 2012.Guidelines for good clinical practice (GCP) for trials on pharmaceutical product. Annex 3 in WHO Expert Committee on Selection and Use of Essential Medicines. Sixth report. Geneva, World Health Organization. 1995 (WHO Technical Report Series, No. 850).Guidelines for good clinical practice (GCP) for trials on pharmaceutical product. Annex 3 in WHO Expert Committee on Selection and Use of Essential Medicines. Sixth report. Geneva, World Health Organization. 1995 (WHO Technical Report Series, No. 850).ICH E6 guideline. Guideline for good clinical practice. Geneva, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1996.ICH E6 guideline. Guideline for good clinical practice. Geneva, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1996.Guidelines on the quality, safety, and efficacy of biotherapeutic protein products prepared by recombinant DNA technology. Replacement of Annex 3 of WHO Technical Report Series. № 814. WHO Expert Committee on biological Standardization. October 2013 (Accessed 23 January 2014).Guidelines on the quality, safety, and efficacy of biotherapeutic protein products prepared by recombinant DNA technology. Replacement of Annex 3 of WHO Technical Report Series. ¹ 814. WHO Expert Committee on biological Standardization. October 2013 (Accessed 23 January 2014).Руководство по проведению клинических исследований лекарственных средств (иммунобиологические лекарственные препараты). Часть первая. М.: Гриф и К, 2012.Guideline for conducting clinical trials of drugs. v. I. Moscow: Grief and K. 2012; 244 p. (in Russian).Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008; 117(2): 244-79.Tracey D1, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008 Feb; 117(2): 244–79.

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