Biosimilars in 3D

Recombinant DNA-derived biopharmaceuticals are structurally complex proteins derived from genetically modified living cells or organisms that are difficult to characterize. Because of inherent variability in the biological system and the manufacturing process, any biologic will exhibit microheterogeneity—that is, there will be a certain degree of variability even between different batches of the same product. Several biological products have lost patent protection in recent years, particularly in Europe and to a lesser extent (but soon to change) in the United States (US). This, in turn, has created significant clinical and economic opportunities for pharmaceutical companies to develop and seek marketing authorization for a number of biopharmaceuticals [e.g., human growth hormone, erythropoiesis-stimulating agents [ESAs], granulocyte colony-stimulating factors (GCSFs)]—and in the not-so-distant future, insulin, interferon β, recombinant follicle stimulating hormone and various monoclonal antibodies.1-3 Drawing upon our work on the clinical efficacy and safety of biosimilar recombinant human erythropoietin4-8 and filgrastim,9-11 as evidenced in registration trials and post-approval studies, we review here three issues of relevance to the bioengineering field: (1) definition, (2) development and (3) differentiation of biosimilars. For the purpose of this article, we limit the scope to biosimilar ESAs and GCSFs already approved by the European Medicines Agency (EMA) because, to date, the US Food and Drug Administration (FDA) has not approved a biological product as biosimilar or interchangeable. A few product reviews have been accepted under the FDAs conventional Biologics License Application (BLA) pathway, including the GCSF Tbo-filgrastim, which is the same agent as XM02 approved by the EMA. Epoetin theta was approved by the EMA as a stand-alone product. It is technically not considered a biosimilar by some12 but is practically and clinically viewed by others as such.4,13 There are biosimilars produced in less regulated markets; however, they are not considered in this article.