A large volume of comparative trials including preclinical and clinical data is required to demonstrate automatic substitution (EU terminology, or interchangeability by US terminology) as biosimilar product is developed by a different manufacturer using a different manufacturing process.
Since there is no official position on interchangeability of a biosimilars at the EU level, several EU national regulatory authorities developed their national positions on interchangeability. These agencies’ staff recently expressed possible issues and EU perspectives for biosimilars in the article published in BioDrugs journal.
Immunogenicity can be an issue when switching from reference biologic product to it’s biosimilar, but currently, the probability of acute hypersensitivity to biosimilar is near to zero as amino-acid sequence of both reference and biosimilar products is the same. However, manufacturing change can lead to lack of similarity and therefore in immunogenicity, and such subtle loss of interchangeability has been reported earlier. Several examples are reviewed by authors, but they still conclude that the risk of exaggerated immune reactions as a result of switching between a biosimilar and its reference products is substantially overrated.
Switching from a reference product to its biosimilar versions has been extensively studied for various products in modern randomized controlled trials with crossover design. These trials successfully demonstrated efficacy, safety and interchangeability of biosimilars. Analysis of EudraVigilance database reveals only 3 case reports that can possibly link adverse reactions to switching from reference to biosimilar product.
Considering all the evidence and pharmacovigilance data, authors conclude that further need for such trials is questionable, and the necessity to conduct such trials may discourage biosimilar development. Moreover, these trials assume increase sample size to achieve sufficient power taking the switching into account and adjusting for confounders. In the EU, no specific switching studies are required by legislation or by regulatory guidelines.
A state-of-the-art demonstration of biosimilarity, along with intensified post-marketing surveillance, is a sufficient and realistic way of ensuring interchangeability of EU-approved biosimilars under supervision of the prescriber.
While EU regulatory bodies support the current vision, industry can feel confident that there will be no further increase in either complexity or costs for biosimilar development.