The extrapolation of indications for a biosimilar consists in the regulatory approval of the biosimilar drug for the treatment of diseases that have not been specifically studied during the development of the same. Said approval is only possible if its biosimilarity has been demonstrated and if the mechanism of action is the same among the different indications pending extrapolation. The concept of extrapolating indications is widely recognised worldwide by the main regulatory bodies, such as the World Health Organization (WHO), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (1-3), and is a routine procedure used for most treatments.
Most of the guidelines approved by the regulatory bodies share the same basis for the extrapolation of indications: an extensive analytical comparability exercise, which must include the characterising data of the molecule, its potency and/or in vitro assays covering the functionality of the same, which will be completed with the final step of this exercise: relevant clinical data (4-6). The product’s mechanism of action and the physiopathological mechanism(s) involved in the therapeutic indications studied should be supported with scientific publications regarding the reference medicinal product and should be vastly similar in terms of their indications (7).
Extrapolation is a concept that is closely linked to biosimilarity (8), requiring an understanding of the biosimilar. When the biosimilar has proven to be comparable to the reference in terms of its physicochemical and structural characteristics and in vitro biological functions, the expectation is that it will behave the same in clinical practice.
In this final step of the biosimilarity study, it is important to understand that the role played by clinical studies is purely confirmatory (9). Clinical studies on a biosimilar do not seek to establish the clinical safety and efficacy profile of the reference product in all the usage conditions for which it is authorised. The reason for this is that the clinical safety and efficacy profile of the reference product is already well known, and the expectation is that a product with the same molecular structure and function will exert the same action as the reference product (10). The biosimilar has previously been shown to have a similar molecular structure and function, and in clinical practice it will basically confirm the absence of significant safety, efficacy and immunogenicity differences in relation to the reference product.
Extrapolating the safety and efficacy of one therapeutic indication to another is possible, albeit not automatic, and is based on the comprehensive analysis of all the available evidence, as well as the appropriate scientific justification.
Thanks to the extrapolation of indications, the number of studies can be reduced and unnecessary clinical trials on humans can be avoided, thereby reducing the costs of drugs and the time required to place them on the market (10).
The regulatory authorities approve a biosimilar based on safety, efficacy and quality criteria that are comparable to the reference drug, thereby representing its equivalence in terms of safety, efficacy and immunogenicity in sufficiently sensitive indications or clinical conditions. This proven comparability enables the extrapolation of indications for the biosimilar with respect to the reference biological medicinal product (11).
- World Health Organization. Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs). 1 Mar 2016. Available at: http://www.who.int/biologicals/mAb_1st_draft_KG_IK_1_March_2016_clean.pdf
- Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry. Available at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf
- European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf
- Committee for medicinal products for human use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005. London, 22 February 2006. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003920.pdf
- European Medicines Agency. Committee for medicinal products for human use. Guideline on similar biological medicinal products. CHMP/437/04. London, 30 October February 2005. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf