Abstract by Louise Christine Druedahl
Regulatory approval of biosimilars, i.e., highly similar versions of originator biological products (the reference products), came about to foster competition and lower drug prices; however, the degree to which these goals have been achieved varies. Biosimilars provide opportunities to relieve healthcare system budgets and increase access to medicines, but reported challenges for these products include trade secret protection and complex manufacturing processes.
This PhD research is based within regulatory science but applies a cross-disciplinary approach by integrating knowledge about therapeutic proteins and their manufacturing, patent and trade secret protection, regulatory science, and pharmaceutical policy.
The overall aim of this thesis is to investigate how medicines agency regulators and the pharmaceutical industry view the current and future European regulatory landscape of biosimilar development and approval. The specific aims are:
- To identify key scientific, legal, and regulatory challenges in biosimilar development and their effect on biosimilar market entry (Study I).
- To determine the value and necessity of the European biosimilar clinical comparability trial requirements for establishing biosimilarity (Study II).
- To investigate the current European regulatory practices and the science underpinning interchangeability (Study III).
A qualitative approach was used to collect expert knowledge from medicines agency regulators and the pharmaceutical industry. Empirical data were collected from September 2018 to August 2019 via semi-structured, in-depth interviews for the conduct of the three studies. Twenty-three interviews were conducted with 25 participants, hereof eight EU national medicines agency regulators and 17 company participants. Sampling was purposeful and the participants were recruited using networking and snowballing as sampling strategies. Content analysis was applied by two analysts and audited by a third researcher.
According to the participants, establishing biosimilarity for recombinant proteins is not scientifically challenging if there is access to biotechnology expertise. Further, that trade secrets are surmountable barriers to biosimilar development, but that patents are obstacles because of the large number of patents protecting each biological product. This is particularly relevant regarding the lack of an efficient search mechanism, a lack that leaves biosimilar developers with considerable uncertainty about the patent landscape protecting originator biologics.
Regarding the current regulatory requirements, participants predicted that the clinical trial requirements for comparable efficacy will be reduced. The arguments for and against this were both a matter of science and of aspects of competition, ethics and physicians’ trust. Currently, the scientific discussion is fueled by advances in analytical testing of recombinant proteins and the knowledge generated from former biosimilar approvals.
Interchangeability was also a topic widely focused on by participants, who saw interchangeability as relating to regulatory practices, formal competences and trust and not only as a matter of science of likeness between two biological molecules. Biosimilar switching was largely supported by the participants. Some participants perceived substitution of biologics as an unexplored area filled with unknown potential risks, while others believed that there is sufficient scientific evidence to support it. According to the participants, the lack of scientific clarity of interchangeability might be resolved if the EMA, based on their expertise from biosimilar approvals, could hold a scientific and advisory opinion on interchangeability. The participants disagreed on whether EU countries should allow substitution of biologics; however, the company participants and most regulators were not in favor of this.
The European regulation of biosimilars is a success; nevertheless the participants from European national medicines agencies and the pharmaceutical industry portray a picture of biosimilars as a diverse and complex field undergoing rapid change. The current regulation may undergo changes regarding the biosimilar clinical trial requirements. Further, the European regulation of biosimilars is expected in the future to contain regulation for approval of biosimilars of recombinant orphan drugs; however, changes to the existing framework are likely to be needed for the next generation of follow-on products to gene- and cell-based therapies. Regulatory clarity on interchangeability of biosimilars would be a fruitful next step to ensure scientific grounds for either embarking on or refraining from realizing substitution of biologics in the near future.