HPE HPE Fresenius Kabi handbook - Page 9

DEVELOPMENT Concepts and principles: Development in depth In this article, key concepts and principles in the evaluation and approval of biosimilars are explained Olga Delgado Sanchez PharmD Head of Pharmacy Department, Coordinator of Pharmacy, Health Products and Medicines Policy, University Hospital Son Espases, Palma de Mallorca, Spain The European Medicines Agency (EMA) defines a biosimilar as a biologic medicine that is similar to an original medicine that has already been authorised for use in terms of quality characteristics, biological activity, safety, and efficacy. 1,2 Core concepts in the development of biosimilars include: • Extrapolation • Comparability • Immunogenicity • Interchangeability/risk assessment • Timelines. Extrapolation Extrapolation is a key issue of biosimilar development and relates to extending the findings from one set of conditions to another, such as extending and applying the safety and efficacy data from clinical studies regarding one indication (medical condition) to another indication, or extending data from clinical studies in one population (for example, adults) to another (for example, children). Extrapolation concerns four different aspects – efficacy, safety, immunogenicity and interchangeability – and might relate to the indication, population or both. Much debate has centred on which data are required to grant an approval for the extrapolated indications of the reference product. 1,3 In clinical testing, regulators want to confirm the similarity of the molecules in disease indications; they do not TABLE 1 Rationale for indication extrapolation • Extrapolation is possible based on the overall evidence of comparability provided from the comparability exercise and with adequate justification • If pivotal evidence for comparability is based on pharmacodynamics and different mechanisms of action (or uncertainty exists) for the claimed indications, then applicants should provide relevant data to support extrapolation to all claimed clinical indications • Extrapolations should be supported with a comprehensive discussion of available literature including the involved antigen receptor(s) and mechanism(s) of action want to reassess the clinical benefit of the drug per se. European guidance states that, if adequately justified, biosimilars can receive all authorised indications of the reference product, even though comparative clinical data are only provided for a subset of those authorised indications. 3–6 Extrapolation is possible based on the overall evidence of comparability provided from the comparability exercise and with adequate justification. If pivotal evidence for comparability is based on pharmacodynamics, and different mechanisms of action are relevant (or uncertainty exists) for the claimed indications, then relevant data to support extrapolation for all the clinical indications claimed are required. Applications for extrapolations should also be supported by comprehensive discussion of the available literature, including the involved antigen receptor(s) and mechanism(s) of action. The scientific justification of extrapolation should address: • mechanism of action • biodistribution • immunogenicity • expected toxicities in each patient population. Additionally, any other factor that might affect the safety, efficacy, or immunogenicity of the product in each (approved or claimed) indication should be addressed. Supporting clinical data in a sensitive and representative population are therefore critical to justify extrapolation to other indications. This is a crucial consideration, because if clinical trials were to be conducted in each indication, the breadth of biosimilar development programmes would effectively negate the advantages of an abbreviated approval pathway based on developing a product that is highly similar to a reference product with an established risk–benefit profile. 7 Table 1 shows rationale for extrapolation as indicated by the European Medicines Agency (EMA). Understanding the manufacturing process To better understand the reasoning behind the approval process allowing for the extrapolation of indications, the biosimilar manufacturing process must be fully understood (for further details refer to to the article on manufacturing in this handbook). Biosimilars are systematically engineered to match the reference product in both structure and function. Process optimisation toward similarity and precise control during manufacturing to maintain similarity are important to ensure the quality of biosimilars, as is employing suitable test systems, especially those yielding the best results for hospitalpharmacyeurope.com | 2019 | 9