Pharmaceutical Regulators Propose Principles for Indication Extrapolation for Biosimilars

08 September 2016

Pharmaceutical Regulators Propose Principles for Indication Extrapolation for Biosimilars

September 8, 2016


The IPRF was created as a safe harbor for discussion and promotion of harmonization among regulatory authorities and Regional Harmonization Initiatives (RHIs), including 11 regulators, such as the US Food and Drug Administration, the European Medicines Agency, Swissmedic, Health Canada and Japan’s Pharmaceutical and Medical Devices Agency, among others.

The IPRF BWG suggests that such member organizations consider the proposed principles in the reflection paper on the extrapolation of indication(s) in the authorization of biosimilars.

The paper addresses the issues associated with the extrapolation of indications, proposes principles for extrapolation and considerations of the proposed principles in the approval of biosimilars.

It also includes the proposed scope of regulatory submissions for a biosimilar applicant to receive the approval of an extrapolated indication(s), though it stops short of defining biosimilar terminology, the regulatory requirements in demonstrating biosimilarity or other issues on the authorization of biosimilars that are subject to the policies and procedures of each member regulator.


The authors note that extrapolation of data is already an established scientific and regulatory principle and helps generic, drug, biologic and biosimilar developers avoid repeating unnecessary indication-specific studies conducted by a reference product sponsor.

But in the context of biosimilars, the majority of regulators are only in agreement with accepting the extrapolation of indication(s) on the basis of the totality-of-evidence approach, while “there appears to be no clear consensus regarding what data should be submitted and how they should reach the conclusion to accept the extrapolation of indication(s) based on that evidence.”


In addition, the IPRF notes that the conclusions on the extrapolation of indication(s) can differ between regulators based on legal, regulatory and/or scientific reasons, which may result in additional development requirements for the biosimilar industry.

The paper adds that biosimilar guidelines released by regulators “are essentially the same in that the extrapolation of clinical efficacy and safety data to other indications of the reference product, not specifically studied during the clinical development of the biosimilar product, would be acceptable on the basis of the comprehensive evidence of similarity data with adequate justification using the totality-of-evidence approach.”

Furthermore, many regulators agree, according to IPRF, that the basis for extrapolation should come from an extensive analytical comparability exercise, including characterization data, potency and/or in vitro assay(s) that cover the functionality of the molecule, and be supplemented by relevant clinical data.

“The extrapolation of safety aspects including immunogenicity would require careful consideration because the immunogenicity could differ among indications in relation to concomitant medications-, patients- or disease-specific factors,” IPRF says.

The paper also outlines specific considerations for the extrapolation of indications, evidence from analytical comparability studies (including a couple summaries of the scientific basis of extrapolation granted for some recently licensed biosimilars), in vitro and/or in vivo functional studies, clinical studies and publicly available information.

The IPRF BWG is seeking comment on the draft document by 5 November.

Draft Reflection Paper on Extrapolation of Indications in Authorization of Biosimilar Products

Source: RAPS