Extrapolation of clinical data for multiple biosimilar indications

Extrapolation is a scientific and regulatory principle that refers to the approval of a biosimilar for use in an indication held by the reference product but not directly studied in a comparative clinical trial with a biosimilar. Extrapolation of efficacy and safety data from one indication to another may be considered if biosimilarity to the reference product has been shown by a comprehensive comparability program, including safety, efficacy, and immunogenicity in a key indication that is suitable to detect potentially clinically relevant differences, and there is sufficient scientific justification for extrapolation. Extrapolation of data is an established scientific and regulatory principle that has been exercised for many years.

Why extrapolation?

Extrapolation is essential to biosimilar development. In addition to helping streamline the approval process, extrapolation makes it possible to avoid studies unnecessary for regulatory approval and to allocate resources to areas where studies may be more valuable. Extrapolation may also reduce development costs, thereby making valuable medicines potentially more accessible to patients.

Establishing and confirming biosimilarity, together with product-specific scientific justification, are central to the extrapolation of indications for biosimilars

The totality of evidence demonstrating biosimilarity and scientific justification are crucial to the regulatory approval for extrapolation. While clinical studies play a supporting role, analytical studies are an essential tool for establishing biosimilarity and are typically more sensitive than traditional clinical endpoints in this respect. Over the past 20 years, there has been a 10 million-fold increase in the sensitivity of some analytics. Because of this, many relevant structural components and functions of even a monoclonal antibody can now be determined with high sensitivity, and the structure-function relationships determined. In addition to the data from the totality of evidence, experience with the reference biologic is used to support extrapolation.

Biosimilars Pathway

Extrapolation requires scientific justification

Aspects that may be considered for scientifically justifying extrapolation may include mechanism of action (MOA) in each indication, PK and biodistribution, expected toxicities, and any other factor (such as comorbidities). Thus, extrapolation is not automatic and is considered only after biosimilarity is established based on the totality of evidence.

Key aspects that may be considered for extrapolation