Biopharmaceuticals as Challenges to the Regulatory System

Abstract

Biopharmaceuticals differ from small molecules in terms of structure and pharmacology. Furthermore, they are also prescribed for different patient populations. The protein nature of biopharmaceuticals makes them especially prone for immunological reactions and their safety profile may be affected by seemingly minor changes in the production process. This unpredictability of safety concerns of biopharmaceuticals has triggered increased regulatory interest in the safety of biopharmaceuticals, which has increased as a result of the arrival of competing version of biopahrmaceuticals, so-called ‘biosimilars’. In thesis biopharmaceuticals are studied as challenges to the regulatory system, through the analysis of safety concerns of biopharmaceuticals and the ability of existing regulatory instruments to deal with these issues. This thesis is divided in three chapters covering different themes: (1) mechanisms of adverse events of biopharmaceuticals and the consequences for risk management strategies, (2) challenges posed by the arrival of biosimilars and (3) strategies to study regulatory processes. Novel regulatory and pharmacovigilance tools have provided regulators with new tools to optimize risk management of biopharmaceuticals. We have found that, despite clear differences in the nature of post authoroziation safety events between biopharmaceuticals and small molecules, these differences were not reflected by differences in the source of these regulatory actions. The knowledge that has been gained with biopharmaceuticals is being translated into tools to facilitate their safety management. Based on the knowledge of a product, how it interacts with its target, and likely immunological ADRs, a carefully designed pharmacovigilance strategy taking a case-by-case approach should determine the optimal toolkit to establish the benefit risk profile of biopharmaceuticals. European regulations outlining the approval criteria for biosimilars have been in place since 2005 and since then 14 biosimilar products have received marketing authorization. Several questions remain about their safety profile and they are subject to extensive post authorization requirements. We argue that the scope of post authorization risk management should be limited to immunogenicity associated adverse events. We reviewed several data sources and did not identify safety events associated with switching between biopharmaceuticals within the same class. We identify that challenges remain to develop biosimilars in oncology, in order to allow the development of biosimilar monoclonal antibodies it may be necessary to identify novel endpoints of the comparability exercise. We evaluated the role of periodic safety update reports (PSURs) as regulatory instruments to monitor the safety of biopharmaceuticals. We found that it remains a challenge to determine their contribution to the safe use of medicines as ancillary to existing pharmacovigilance requirements. Furthermore we performed a cost effectiveness analysis of PSUR reporting for biopharmaceuticals in Europe. Our data suggest that it is unlikely that the costs of PSUR reporting for biopharmaceuticals outweighed its health gains. We conclude that regulations should be standard accompanied with a plan to assess their effects. We present a model that may be instrumental in gaining insight in the efficiency of regulatory instruments in achieving predefined objectives and to monitor the performance of new and/or existing regulatory requirements.