Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The issue of extrapolation of indications in the registration of biosimilars ***

Ellen Scheibe (Abschlußjahr: 2016)

Summary
Language: English
Extrapolation is an established procedure in regulatory practice. It is in many ways necessary to draw conclusions from a limited set of data in order to make meaningful decisions. It strives to avoid unnecessary or unethical studies by building on existing knowledge. In the context of the approval of biosimilars, however, the concept of extrapolation of indications has become a controversially debated issue between regulators and clinicians and other stakeholders of the health care system. This debate has significantly intensified since the approval of the first biosimilars of monoclonal antibodies, which represent particularly complex molecules, offer highly targeted medical treatments and are exceptionally lucrative drugs. This Master Thesis introduces the development and status of the regulatory framework for the extrapolation of indications in the licensing of biosimilars with a focus on the pioneering role of the European Medical Agency (EMA) and analyzes the controversy triggered by it.
In the first part of this thesis, the general concept of extrapolation in regulatory review is described. It is explained why and in which situations extrapolation is frequently used in regulatory practice. The initial emphasis on extrapolation across age-groups particularly in paediatric investigation plans is introduced, which may foster attempts to define a general framework and well defined algorithms for extrapolation in all areas of drug development. This may include the extrapolation of data into indications, which are lacking the direct evidence of a biosimilar’s therapeutic benefit from pivotal clinical studies.
The second part gives an overview on the current regulatory thinking about the extrapolation of indications for biosimilars. It defines why bioequivalence studies as required for generics are not sufficient in the assessment of biosimilars. It explains why even originator biologicals need to undergo thorough comparability exercises to ensure their validated quality and links this with the biosimilarity approach. Based on that, an account of the regulatory guidance in the EU with regard to biosimilars is given, focusing on provisions for the extrapolation of indications, amended by a view on WHO guidelines and regulations in other key countries. Additionally, the most recent revisions of the overarching European biosimilar guidances are summarized.
The third part illustrates these more theoretical considerations by the example of the first monoclonal antibody biosimilar whose approval for all indications of its originator infliximab by the EMA (and other regulatory authorities) led both to disagreements with some other regulators (namely Health Canada) and to severe concerns of clinicians. In this context, the specific issues at stake – mode of action, pathophysiological differences, sensitivity of the pivotal clinical study’s indication – are highlighted as well as the problem of switching treatment of patients from the originator to the biosimilar infliximab.
Finally, the reasons for the different paradigms of regulators and clinicians in judging drug development data in general and in assessing the extrapolation of indications in particular are discussed. There is a wide consensus among regulators that the clinical benefit of a biosimilar has already been established in the clinical development program of its originator. Therefore the very sensitive and specific proof of essential similarity in the sense of the absence of differences is mostly sufficient to support the extrapolation of indications.
Pages: 45 plus 20 pages annex