Biosimilar and interchangeable: Inseparable scientific concepts?

As defined by the European Commission, the term interchangeability refers to “the possibility of exchanging one medicine for another that is expected to have the same clinical effect.” In the context of biosimilars the term interchangeability has caused confusion. Likely due to specific regulatory requirements in the United States, physicians sometimes interpret interchangeability as the potential for a biologic to be substituted by a biosimilar at the pharmacy level, without the involvement of a physician. However, interchangeability between a biological reference medicine and a corresponding biosimilar medicine should not be defined by its practical application; whether physician‐driven switch or pharmacist‐driven substitution. Interchangeability, ie, the possibility of safely and effectively changing a reference medicine by its biosimilar, or vice‐versa, in a given patient, should be rather recognized as a scientific concept. In this paper, we review the evidence supporting the assertion that interchangeability is inherent to biosimilarity. In science, a conclusion is reached when a hypothesis is tested by the use of an appropriate experimental approach. The aim of biosimilar development is to replicate an existing biomedicine. Biosimilarity must be substantiated by robust scientific evidence. To generate such evidence, a hypothesis of high similarity between a biosimilar candidate and the original reference medicine should be verified through well‐ established and validated methodologies that aim to identify all the potential relevant physicochemical differences, but are also capable of detecting even clinically meaningless differences. The acceptable difference level between the biosimilar candidate and the reference medicine is determined to a qreat extent by a thorough assessment of multiple batches of the reference biologic. Indeed, no approved biological medicine, whether original or not, is structurally identical to itself, due to an intrinsic batch‐to‐batch variability that can be enhanced by manufacturing changes. Although different batches of reference biological compounds are not identical to each other, they may be considered essentially equal and therapeutically indistinguishable. Therefore, there is a clinically acceptable range of inherent structural heterogeneity for any biological product. As a consequence, many patients have likely been treated with structurally slightly different versions of any given reference biomedicine, which constitutes a de facto switch of insignificant therapeutic concern. The approach used to substantiate biosimilarity represents a refinement of the procedures that have been securely applied for decades to batches of biologics that are subject to manufacturing changes, but also to the very precise discrimination between native and non‐native proteins during the monitoring of