A complex affair

To date, the European Medicines Agency (EMA) has authorised 27 biosimilars across the EU, the most recent of which is Merck Sharp & Dohme’s Lantus biosimilar, Lusdana (insulin glargine), on 4 January 2017. Expiration of the patents for many branded biologics has been a significant driver of biosimilars development, as has the high cost of the branded versions. To obtain a marketing authorisation, developers need to establish similarity to the reference product in terms of quality characteristics, biological activity, and safety and efficacy, based on a comprehensive comparability exercise.

Navigating the complexities of biosimilar development is challenging. Biosimilar clinical trials differ in significant ways from studies on new biologic entities. Because the clinical profile of the reference compound is already known, some key elements, such as proof-of-concept and overall risk–benefit profile, do not need to be re-evaluated for the biosimilar. Therefore, the amount and type of clinical data will constitute a smaller part of the regulatory submission package than for new entities. The main objective of a biosimilar clinical programme is thus not to re-demonstrate clinical efficacy per se but to address bioequivalence and any residual uncertainty about the biosimilarity of the candidate following the completion of physicochemical and biological characterisations and in vivo studies, where appropriate.

Extrapolation is a core principle 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 to another indication, or extending data from clinical studies in one study population to another (for example, adults to children). Extrapolation concerns four key aspects – efficacy, safety, immunogenicity and interchangeability (that is, changing one medicinal product for another that is expected to achieve the same outcome in a given clinical setting and in any patient) – and may concern the indication, the population, or both. European guidance states that, if adequately justified, biosimilars may receive all authorised indications of the reference product, even though comparative clinical data are only provided for a subset of those authorised indications. Much debate has focused on which data are required to grant an approval for the extrapolated indications of the reference product.

The EMA is due to launch a pilot project in February 2017 to test the value and feasibility of providing tailored scientific advice for the development path of biosimilar medicines. The aim of this new initiative is to provide biosimilar manufacturers with advice on the studies/tests they should be conducting, on the basis of the quality, analytical and functional data that is already available for the reference product. It is expected to better support the stepwise development of biosimilars that is recommended in EU guidelines. According to this method, the extent and nature of the studies/tests required depend on the level and robustness of data already collected. As part of this pilot, an in-depth review of the quality, analytical and functional data available will be performed. Advice will be given on the basis of the data submitted, thereby allowing for more tailored recommendations on the studies and tests that should be carried out in the next steps of the development. The pilot is open to all companies seeking scientific advice for the development of a biosimilar and any type of biosimilar will be accepted into the scheme.

Boehringer Ingelheim’s BI 695501, its adalimumab biosimilar candidate to Humira®, was accepted for regulatory review by the EMA and FDA in January 2017. It is hoped that BI 695501 will provide a valuable treatment option for patients affected by inflammatory diseases. Hospital Pharmacy Europe has recently worked with Boehringer Ingelheim to develop the educational handbook entitled: Biosimilars: An evolving paradigm in the therapeutic landscape, which will be distributed with issue 84 to provide hospital pharmacists with all they need to know about regulatory issues, clinical development, EU and US legislation, and sustainability of biosimilars in healthcare systems.