Comparative Studies of Biosimilar Medicinal Products

The article describes specific aspects of biosimilars research and development. The aim of the study was to analyse the ways to conduct comparative studies of biotechnological medicinal products and the main approaches to the assessment of the obtained data. The paper highlights that biotechnological products are associated with a much higher potential variability of chemical and pharmacological characteristics than small molecules. The author analyses the reasons of this phenomenon, describes mechanisms underlying the microheterogeneity of protein molecules, primarily post-translational modification. The latter has an impact on the pharmacokinetic parameters, pharmacodynamics and immunogenicity of complex protein molecules, which increases the variability of test results and makes it difficult to conduct bioequivalence studies. In addition to bioequivalence studies, biosimilars research should include comparative studies of pharmacodynamics, evaluation of therapeutic equivalence and immunogenicity. Assessment of the medicines comparability should be based on the analysis of all data provided, which requires a more flexible and sometimes individual approach on the part of regulatory authorities.

1. Schiestl M, Zabransky M, Sorgel F. Ten years of biosimilars in Europe: development and evolution of the regulatory pathways. Drug Des De-vel Ther. 2017;11:1509-15. https://doi.org/10.2147/DDDT.S130318

2. Mielke J, Jilma B, Jones B, Koenig F. An update on the clinical evidence that supports biosimilar approvals in Europe. Br J Clin Pharmacol. 2018;84(7):1415-31. https://doi.org/10.1111/bcp.13586

3. Warren JB. Generics, chemisimilars and biosimilars: is clinical testing fit for purpose? Br J Clin Pharmacol. 2013;75(1):7-14. https://doi.org/10.1111/j.1365-2125.2012.04323.x

4. Walsh G, Jefferis R. Post-translational modifications in the context of therapeutic proteins. Nat Biotechnol. 2006;24(10):1241-52. https://doi.org/10.1038/nbt1252

5. Knorre DG, Kudryashova NV, Godovikova TS. Chemical and functional aspects of posttranslational modification of proteins. Acta Naturae. 2009;1(3):29-51. PMID: 22649613

6. Eleryan MG, Akhiyat S, Rengifo-Pardo M, Ehrlich A. Biosimilars: potential implications for clinicians. Clin Cosmet Investig Dermatol. 2016;9:135-42. https://doi.org/10.2147/CCID.S91691

7. Camacho LH, Frost CP, Abella E, Morrow PK, Whittaker S. Biosimilars 101: considerations for U.S. oncologists in clinical practice. Cancer Med. 2014;3(4):889-99. https://doi.org/10.1002/cam4.258

8. Waller CF, Vutikullird A, Lawrence TE, Shaw A, Liu MS, Bacz-kowski M, et al. A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL-1401O vs. EU-trastuzumab and US-trastuzumab. Br J Clin Pharmacol. 2018;84(10):2336-43. https://doi.org/10.1111/bcp.13689

9. Knight B, Rassam D, Liao S, Ewesuedo R. A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers. Cancer Chemother Pharmacol. 2016;77(4):839-46. https://doi.org/10.1007/s00280-016-3001-2

10. Schoergenhofer C, Schwameis M, Firbas C, Bartko J, Derhaschnig U, Mader RM, et al. Single, very low rituximab doses in healthy volunteers — a pilot and a randomized trial: implications for dosing and biosimilarity testing. Sci Rep. 2018;8(1):124. https://doi.org/10.1038/s41598-017-17934-6

11. Markus R, Liu J, Ramchandani M, Landa D, Born T, Kaur P. Developing the totality of evidence for biosimilars: regulatory considerations and building confidence for the healthcare community. BioDrugs. 2017;31(3):175-87. https://doi.org/10.1007/s40259-017-0218-5

12. De Mora F. Biosimilar: what it is not. Br J Clin Pharmacol. 2015;80(5):949-56. https://doi.org/10.1111/bcp.12656