Perspectives Biosimilars: the science of extrapolation

Since the establishment of a specific approval pathway for similar biological medicinal products, so-called “biosimilars,” several biosimilars have been licensed and become available in the European Union (EU). However, despite a stringent approval process, acceptance of biosimilars in the medical community continues to be low. This appears to be especially true for therapeutic indications, for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. Several learned societies have issued statements discouraging the use of biosimilars in such “extrapolated” indications. The reasons for this distrust may be manyfold. The frequently cited paradigm that biosimilars are “similar but not identical,” compared with the “identicality” principle of the more familiar small-molecule generics, appears to be confusing and may leave physicians uneasy about remaining uncertainties with respect to efficacy and/or safety of the biosimilar. In addition, clinicians tend to mainly look at clinical trial data to judge the efficacy and safety of a medicinal product, whereas the foundation of any biosimilar development is the extensive characterization and comparison of structural and functional characteristics using stateof-the-art analytical tools. Inconsistent use of terminology and fears arising from problems reported on biologicals licensed in other regions of the world and erroneously called “biosimilars” may also contribute to the wrong perception that biosimilars in general may not be sufficiently studied and may not be safe. Finally, clinicians simply may not be well informed about the scientific concept underlying the development and licensing of biosimilars. This article specifically addresses the concerns raised about the use of biosimilars in extrapolated indications and explains the underlying science and regulatory decision making, including some real-life examples from recently licensed biosimilars. This article is an extension to a previous paper in which we explained the principles of biosimilar development in general. The similar-but-not-identical paradigm