IPRF Principles for Biosimilar Indication Extrapolation

The Biosimilar Working Group of the International Pharmaceutical Regulators Forum (IPRF) has published for comment a “reflection paper” proposing principles on the extrapolation of indications in the authorization of biosimilar products. (FDA is a member of the IPRF.)

The paper suggests that the extrapolation of indications of a biosimilar product could be accepted “on the basis of the totality of the evidence generated from analytical, non-clinical, and clinical comparability data. It is expected that the safety and efficacy can be extrapolated when biosimilar comparability has been demonstrated through physiochemical, structural, and biological analysis as well as appropriate clinical data in one therapeutic indication and that the mechanism of action is the same or sufficiently similar across the extrapolated indications. Additional data are required when residual uncertainty remains which could impact on clinically meaningful differences between the biosimilar and the reference product.”

The working group says that extrapolation of data is already an established scientific and regulatory principle that has been exercised for many years, such as with major changes in the manufacturing process of originator products. It notes that for biosimilars, the majority of national regulatory agencies that are IPRF members agree with accepting the extrapolation of indications on the basis of the totality-of-evidence approach, but there is no clear consensus on what data should be submitted and how the agencies should reach a conclusion to accept the extrapolation of indications based on that evidence.

The paper’s general considerations cover principles for demonstrating biosimilarity first and then principles for extrapolating indications. It says that the comparability exercise for demonstrating biosimilarity should be based on head-to-head comparisons of the proposed biosimilar and its reference product in terms of analytical, non-clinical, and clinical studies to demonstrate similarity in quality, safety, and efficacy.

“The purpose of a clinical comparative study to demonstrate biosimilarity is not to independently reestablish the safety and efficacy of the proposed biosimilar product,” it says, “but to support the evidence that the proposed biosimilar is highly similar to its reference product, thereby providing assurance there are no clinically meaningful difference between them.”

The document suggests that these factors be considered for justifying the extrapolation of indications: 

•          whether the tested therapeutic indication is the most sensitive for detecting differences in relevant aspects of efficacy and safety;
•          whether the individual receptors and/or clinically relevant mechanisms of action are the same;
•          the fact that in some agency guidelines, emphasis is placed on the mechanisms of the diseases or conditions involved and clinical experience with the reference product; and
•          any factors that may affect the safety profile, including immunogenicity in each condition of use and patient population.