Can the Biosimilar Concept be Applied to Complex Proteins?
The biosimilars approved under the current EU process are just the beginning of a global biosimilar revolution. A host of other products – including follow-on monoclonal antibodies – are already in development, and will probably be submitted to regulatory agencies in the years ahead. Those potential products raise a critical question: Can the biosimilar concept be applied to more complex proteins?
Recent advances in biological science provide powerful tools to characterize complex proteins down to the atomic level. These technologies make it theoretically possible to demonstrate physical, chemical, and biological similarity for virtually any highly purified protein. With that data, biosimilar manufacturers should be able to gain insight into the biological effects of follow-on proteins compared with a reference product.
The next step in demonstrating biosimilarity requires leveraging current knowledge and filling the gaps by conducting appropriate non-clinical and clinical studies. Even for small-molecule generics, bioequivalence in terms of absorption must be demonstrated through clinical studies. Additional data will be required to demonstrate equivalence for biosimilars. In keeping with the evolving World Health Organization (WHO) guidelines, regulators will no doubt demand evidence of equivalent efficacy and adequate safety (as the EU already does), which will require clinical trials.
The size of the required clinical program will depend on the level of understanding about the protein structure, the impurity profile, and other characteristics, as well as the ability to demonstrate therapeutic equivalence. In some cases, a biosimilar clinical program may require more patients than the innovator trials. At the same time, sponsors will have the benefit of knowledge about the innovator drug’s patient experiences, and the relationship between pharmacodynamics, dose, and therapeutic response. This information can be used to steer the development of a biosimilar.
While the development of more-complex biosimilar proteins may be more challenging than simpler products, there is no compelling reason why most biologicals should not qualify. Modern production methods and analytical techniques have evolved to a level that allows the production of highly similar monoclonals and other complex proteins. Equally important, having no biosimilar approval pathway for complex proteins would make development of follow-on versions of such products impractical. However, sponsors will need to plan their trials carefully, working closely with external experts and the regulatory agencies to determine the most appropriate requirements of a biosimilar clinical program on a case-by-case basis so as to demonstrate therapeutic and safety equivalence.