Biosimilars in European Union: State of the Art

Biosimilars are biological medicinal products marketed as a copy of an originator (reference) product to which they are similar but not identical. Today, biosimilars are a reality of the pharmaceutical market in the European Union. The scenario is complicated by evolving regulatory policies, mainly established by guidelines issued by EMA, and periodically revised to reflect the experience gained. Unlike generics, which contain the same (small molecule) active substance(s) as that of a reference medicinal product and have a bioequivalence demonstrated through appropriate bioavailability studies, biosimilars, are demonstrated to be similar but not identical to their reference products. Indeed, their chemical characteristics are directly related to the manufacturing process, and cannot be precisely duplicated, due to the strong relationship between the manufacturing processes of biopharmaceuticals and the characteristics of the final product. Moreover, since no analytical techniques are currently available for detecting or predicting all biological and clinical properties of proteins, differences between biopharmaceutical products can easily remain undetected. Thus, to grant a Marketing Authorization (MA), biosimilars require an approach different from both originators and generics. The similarity of two biological medicinal products is further complicated by the change of manufacturing processes frequently performed not only during development, but also after approval. Such changes may result in an evolution of quality profile during the product lifecycle, so that the conclusion of a comparability exercise performed at a given time may not hold true for the whole lifecycle. The actual impact of these changes on the product on the market has to be evaluated and a new comparability exercise might be required when the biotechnological active ingredient shows significant variations. Moreover, pharmaceutical companies have the possibility of submitting a given molecule with the characteristics of a biosimilar as a new application (presenting a full dossier) or as an abridged application. This makes the concept of “biosimilarity” even more complicated. These peculiarities can lead to possible issues for substitution and/or interchangeability. The rational of interchangeability is based on the therapeutic equivalence and is related to intrinsic drug characteristics. In contrast, automatic substitution at the dispensing level can be introduced by the Public Administration on the basis of interchangeability. Thus, whether automatic substitution at the dispensing level should be permitted or whether the choice pertains only to the prescribing physician remains an open question. Finally, different products may bring to different adverse events, particularly immunogenicity, so that a specific pharmacovigilance policy has to be required.