Biosimilars: the science of extrapolation

Abstract

Despite the establishment of a specific approval pathway, the issuance of detailed scientific guidelines for the development of similar biological medicinal products (so-called “biosimilars”) and the approval of several biosimilars in the European Union, acceptance of biosimilars in the medical community continues to be low. This is especially true in 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. This article addresses the concerns frequently raised in the medical community about the use of biosimilars in such extrapolated indications and explains the underlying scientific and regulatory decision making including some real-life examples from recently licensed biosimilars.

Biosimilars in oncology and inflammatory diseases: current and future considerations for clinicians in Latin America

“…Pertinent considerations include the mechanism of action of the active substance and the target receptors involved in each indication, and any differences in the safety and immunogenicity profile of the originator between indications. 39 Furthermore, as mentioned above, it is crucial that biosimilarity has been confirmed in a clinical test model that is deemed sensitive for detecting product-related differences; important factors include the patient population (which will determine effect size), endpoint, dosage, and time point used in the efficacy and safety comparison. 40 …”

“…133 There was much debate on the issue of approval for extrapolated IBD indications. 39,134 Therefore, real-world experience with CT-P13 used in IBD has been of particular interest to gastroenterologists. The significant body of post-authorization data published has not revealed any unexpected concerns in this population, 135 validating the regulatory decision to grant approval in the extrapolated indications.…”

“…Biosimilar approval pathways in these markets have been created with the understanding that biosimilars may have a disease-modifying role in serious and life-threatening illnesses, 39 and thus far no significant concerns have arisen in terms of the safety, efficacy, or immunogenicity of biosimilars authorized according to these regulations. 62 The same cannot be said for intended copy biologics approved according to less rigorous standards, and these agents cannot be considered true biosimilars, regardless of the level of clinical experience accrued with them.…”

Clinical considerations for the development of biosimilars in oncology

“…10 A common misconception about extrapolation is that the focus is on the clinical data alone for making the justification. 31 However, since the clinical evidence is only part of the data supporting the regulatory application for a biosimilar, the justification for extrapolation is based on the overall totality of data generated on similarity of the biosimilar to the reference product, including non-clinical data such as analytical and in vitro functional comparisons and the mechanism of action in the indications concerned. Evaluation of a biosimilar for extrapolation to additional indications is conducted on a case-by-case basis and depends on the level of evidence provided by the applicant.…”

A Primer on Biosimilars: FDA-Approved and those in the Pipeline

“…Every biological or biopharmaceutical product displays a certain degree of variability, even between different batches, which is due to the inherent variability of the biological expression system and the manufacturing process [3]. Biosimilar antibodies are "generic" versions of the originally marketed antibodies.…”