The safety of biological preparations. Part 2. Safety issues of biosimilars

The use of the reduced scheme in preclinical and clinical studies of «biosimilars» requires special attention to the safety issues. During the process of the marketing authorization of biosimilars in 2013-2015 the countries with advanced regulatory and pharmacovigilance systems (USA, Canada and EU countries), the most contentious debates were provoked by the issues of extrapolation of the results of the research of a biosimilar infliximab (TNFα-specific monoclonal antibodies). EMA made the decision that the results of the efficacy and safety studies of infliximab, obtained in adult patients with rheumatoid disease, can be extrapolated to the indications for the treatment of inflammatory bowel disease (Crohn’s disease and ulcerative colitis in adults and in children). Several medical associations such as the Association of Gastroenterologists and the Association of Pediatricians believe that this extrapolation is not justified. Health Canada also made a conclusion that the extrapolation is not justified and did not approve the use of the mentioned preparation for the treatment of Crohn’s disease and ulcerative colitis. There is still an ongoing hot discussion on the issue of interchangeability of an original medicine and a biosimilar. Given that the safety of a biosimilar has been studied before obtaining marketing authorization not to the fullest extent, usually safety studies continue after obtaining marketing authorization for a few more years. If there is an interchange of medicines, then it is not possible to objectively evaluate the safety of a biosimilar. In the countries with poor regulatory and pharmacovigilance system not only «biosimilars» are in drug circulation system, but also other medicines registered under the reduced studies scheme, but not in full compliance with the principles of «biosimilarity». The quality of these medicines does not always meet the standards, as evidenced by numerous studies. WHO is concerned about the quality of the mentioned medicines and suggests to call them «non-innovators» and establish a separate group, and claimed that the sponsors were invited for a certain period of time to provide the evidence of the high quality of these medicines.

биоподобные препараты, биоаналоговые препараты, препараты «non-innovators», «biosimilars», экстраполяция результатов, взаимозаменяемость, препараты моноклональных антител, биоаналоговые инсулины, biosimilars, «non-innovators» preparations, extrapolation of the results, interchangeability, preparations of monoclonal antibodies, biosimilar insulins

1. Guideline on similar biological medicinal products (CHMP/437/04 Rev. 1).

2. Guidance for Industry. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. U. S. Department of Health and Human Services Food and Drug Administration. Biosimilarity. February, 2012.

3. Wolfe F, Michaud K. The loss of health status in rheumatoid arthritis and the effect of biologic therapy: a longitudinal observational study. Arthritis Research Therapy 2010; 12: R35–47.

4. Shaw BE, Confer DL, Hwang WY, Pamphilon DH, Pulsipher MA. Concerns about the use of biosimilar granulocyte colonystimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association. Haematol. 2011; 96: 942–7.

5. Barosi G, Bosi A, Abbracchio MP, Danesi R, Genazzani A, Corradini P, et al. Key concepts and critical issues on epoetin and filgrastim biosimilars. A position paper from the Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation. Haematol. 2011; 96: 937–42.

6. Schmitt M, Publicover A, Orchard KH, Görlach M, Wang L, Schmitt A, et al. Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Theranostics 2014; 4(3): 280–9.

7. Declerck PJ. Biosimilar monoclonal antibodies: a science-based regulatory challenge. Expert. Opin. Biol. Ther. 2013; 13: 153–6.

8. Lispi M, Datola A, Bierau H, Ceccarelli D, Crisci C, Minari K, et al. Heterogeneity of commercial recombinant human growth hormone (r-hGH) preparations containing a thioether variant. J. Pharm. Sci. 2009; 98(12): 4511–24.

9. Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, Jootar S, Intragumtornchai T, Tungsanga K, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int. 2011; 80(1): 88–92.

10. EMA. Inflectra: EPAR — Public assessment report. 2013. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR-Public_assessment_report/human/002778/WC500151490.pdf.

11. Ebbers HC, Crow SA, Vulto AG, Schellekens H. Interchangeability, immunogenicity and biosimilars. Nat Biotechnol. 2012; 30: 1186–90.

12. Fiorino G, Danese S. The biosimilar road in inflammatory bowel disease: the right way? Best Pract Res Clin Gastroenterol. 2014; 28: 465–71.

13. de Ridder L, Waterman M, Turner D, Bronsky J, Hauer AC, Dias JA, et al. Use of biosimilars in paediatric inflammatory bowel disease: a position statement of the ESPGHAN Paediatric IBD Porto Group. J Pediat Gastroenter Nutr. 2015; 61(4): 503–31.

14. Fonseca JE, Gonçalves J, Araújo F, Cordeiro I, Teixeira F, Canhão H, et al. The Portuguese Society of Rheumatology position paper on the use of biosimilars. Acta Reumatol Port. 2014; 39: 60–71.

15. Fiorino G, Girolomoni G, Lapadula G, Orlando A, Danese S, Olivieri I. The use of biosimilars in immune-mediated disease: a joint Italian Society of Rheumatology (SIR), Italian Society of Dermatology (SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD) position paper. Autoimmunity Rev. 2014; 13: 751–5.

16. Argüelles-Arias F, Barreiro-de-Acosta M, Carballo F, Hinojosa J, Tejerina T. Joint position statement by “Sociedad Española de Patología Digestiva” (Spanish Society of Gastroenterology) and “Sociedad Española de Farmacología” (Spanish Society of Pharmacology) on biosimilar therapy for inflammatory bowel disease. Rev Esp Enferm Dig. 2013; 105(1): 37–43.

17. Scott BJ, Klein AV, Wang J. Biosimilar monoclonal antibodies: a canadian regulatory perspective on the assessment of clinically relevant differences and indication extrapolation. J Clin Pharmac 2015; 55(S3): S123–32.

18. Ben-Horin S, Yavzori M, Fudim E, Picard O, Ungar B, Lee SY, et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognize the bio-similar Remsima. Gut 2016; 65(7): 1132–8..

19. Gecse K, Farkas K, Lovasz B, Banai J, Bene L, Gasztonyi B, et al. Biosimilar infliximab in inflammatory bowel diseases: first interim results from a prospective nationwide observational cohort. Gastroenter. 2015; 148: S-865–6.

20. EMA. Abasria Insulin glargine: EPAR — Public assessment report. 2014. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion-Initial_authorisation/human/ 002835/WC500169353.pdf.

21. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues (EMEA/CHMP/BMWP/32775/2005 Rev. 1).

22. Heinemann L, Home PD, Hompesch M. Biosimilar insulins: guidance for data interpretation by clinicians and users. Diab Obes Metabol. 2015; 17(10): 911–8.

23. Shestakova MV, Vikulova OK. Biosimilars: presumption of «guilt». Saharny diabet 2011; (4): 91–9 (in Russian).

24. Klimontov VV, Myakina NE. Biosimilar insulin analogues: what we need to know about them. Effektivnaya farmakoterapiya 2015; 1(7): 28–34 (in Russian).

25. EGA. Handbook on biosimilar medicines. 2012. 26. Guidelines on evaluation of similar biotherapeutic products (SBPs). Annex 2. WHO Technical Report Series ¹ 977, 2013.

26. US Food and Drug Administration. Background information: lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. 2014. Available from: http://www.fdagov/Drugs/DevelopmentApprovalProcess/How DrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411424.htm.

27. Niederwieser D, Schmitz S. Biosimilar agents in oncology–haematology: from approval to practice. Eur J Haematol. 2011; 86(4): 277–88.

28. Mellstedt H. Clinical considerations for biosimilar antibodies. EJC Suppl. 2013; 11(3): 1–11.

29. Biological preparations. Position of the Russian Association of Endocrinologists. Saharny diabet 2013; (3): 121–2 (in Russian).

30. Shangin IV, Smirnov AS, Schneider AA. Interchangeability of drugs in Russia: problems and prospects. Sovremennaya organizatsiya lekarstvennogo obespecheniya 2013; (3): 10–18 (in Russian).

31. Vasilenko IA. Interchangeability of drugs: comparative aspects. Razrabotka i registratsiya lekarstvennyh sredstv 2014; 1(3): 146–52 (in Russian).

32. Scott DL, Kingsley G. Clinical effectiveness of biologics in clinical practice. Arthritis Res Ther. 2010; 12(2): 115–6.

33. Mitchell P, Korobelnik P, Lanzetta P, Holz FG, Prünte C, Schmidt-Erfurth U, et al. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol. 2010; 94(1): 2–13.

34. Pe³ka M, Broniarczyk-Dy³a G. Zastosowanie leków biologicznych w dermatologii. Post Dermatol Alergol. 2007; 24(1): 35–41.

35. Shankar S, Handa R. Biological agents in rheumatoid arthritis. J Postgrad Med. 2004; 50: 293–9.

36. Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård U, van den Berg HM. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109(11): 4693–7.

37. Richter B, Neises G, Bergerhoff K. Human versus animal insulin in people with diabetes mellitus: a systematic review. Endocrinol Metab Clin North Am. 2002; 31: 723–49.

38. Belousov DYu. Biosimilars — how are they similar? Kachestvennaya klinicheskaya praktika 2006; (2): 80–3 (in Russian).

39. Ermolenko VM, Filatova NN Mihaylova NA, Hasabov NN. Recombinant human erythropoietin: original drugs and biosimilars. Klinicheskaya nefrologiya 2012; (2): 4–8 (in Russian).

40. Soldatov AA, Avdeeva ZhI, Alpatova NA, Medunitsyn NV, Kiselevsky MV, Lysikova SL, et al. The aspects of biosimilar marketing approval process. Biopreparaty 2014; (4): 24–36 (in Russian).

41. World Health Organization. Regulatory expectations and risk assessment for biotherapeutic products. WHO/RRA BT DRAFT/24 January 2014. Available from: http://www.who.int/biologicals/ WHO_ Risk_Assessment_for_Biotherapeutics_1st_PC_24_Jan_2014.pdf.

42. Owens DR, Landgraf W, Schmidt A, Bretzel RG, Kuhlmann M. The emergence of biosimilar insulin preparations — a cause for concern? Diab Technol Ther. 2012; 14: 989–96. 44. Joshi SR. Biosimilar peptides: need for pharmacovigilance. J Assoc Phys India 2011; 59: 44–7.

43. Kuhlmann MK, Schmidt A. Production and manufacturing of biosimilar insulins: implications for patients, physicians, and health care systems. Biosimilars 2014; (4): 45–58.

44. Friedrichs A, Bohnet J, Korger V, Adler S, Schubert-Zsilavecz M, Abdel-Tawab M. Dose Accuracy and Injection Force of Different Insulin Glargine Pens. J Diabetes Sci Technol 2013; 7(5): 1346–53.

45. Policy statement: Clarifying the appropriate regulatory pathway for subsequent entry low molecular weight heparins. Available from: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/lmwh-pol-3 hfmm-eng.php.

46. Guidance for sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). Published by authority of the Minister of Health. Available from: http://www.hc-sc.gc.ca/ dhp-mps/brgtherap/applic-demande/guides/seb-pbu/seb-pbu_2010- eng.php.