P208: New Trends in Biosimilar Clinical Development
PPD, part of Thermo Fisher Scientific United States
Overview of the regulatory landscape and the new arising trends in biosimilar clinical development.
Overview of the main regulatory requirements in US vs. EMEA along with the overall analysis of the clinical development trends for biosimilars based on direct experience.
The expiration of patents in next 3 to 5 years of several blockbuster biological medications increases the interest on “second” and “third” wave of biosimilars clinical development, meaning there is a real need for simplified/streamlined development plans. This is also supported by new guidance recently published (MHRA) although seems the agencies are not yet prepared for such significant change.
In terms of pharmacokinetics (PK), the most important stage in the stepwise development process is the pivotal Phase I study, which has to be statistically powered to demonstrate PK comparability between the test biosimilar and reference product(s).
Once Phase I trial demonstrates PK comparability, the next and final stage in the stepwise development of biosimilars is typically a large Phase III efficacy trial in the intended patient population. However, the requirement for such efficacy trials is growing increasingly unclear, especially in situations where the mechanism of action is well understood, and a robust PD marker is available in healthy volunteers which is an acceptable surrogate for efficacy. In such circumstances, waiving the Phase III clinical comparability trial may be possible from a scientific standpoint
However, even in light of recent approvals without Phase III trial, some questions remain; for example, would a relatively small single-dose Phase 1 study in NHVs provide sufficient safety and immunogenicity data in highly complex molecules compared to a much longer multiple-dose Phase III trial in patients?
Although PK comparability is comprehensively addressed in Phase I and the key objective of Phase III trials is to compare efficacy, the usefulness of collecting PK data in Phase III should not be overlooked or underestimated. Phase III trials provide a unique opportunity to gain additional PK information in the intended patient population. PK sampling is therefore recommended in all Phase III biosimilar studies.
The expiration of patents in next 3 to 5 years of several blockbuster biological medications will also generate a “second” and “third” wave of biosimilars clinical development, which is expected to expand substantially the future biosimilar market. The experience gathered during these years in the molecular characterization of complex biological drugs and their pharmacokinetic and pharmacodynamic behaviors is prompting manufacturers and regulatory authorities to consider whether the current pathway to approval should evolve towards a more simplified frame without sacrificing the quality and clinical evidences needed to ensure safe and efficacious drugs are approved on the market. Indeed, recent publications provided evidences that biosimilar drugs failed market approval in Europe for gaps in PK/PD data, instead of clinical efficacy that was still confirmed. The British Regulatory Agency MHRA has issued a draft guidance in 2021, where different expectations are described about the need for clinical efficacy studies and similar considerations could be potentially anticipated by the EMA in the next future. While we share the enthusiasm and expectations about this “simplified” pathway and the opportunity to bring biosimilar medications faster to the market, we wonder whether this is going to be a “one-size-fits-all” approach, or if later entries, i.e. the third or fourth biosimilar for the same originator product, will be those benefitting more of this simplified pathway, leveraging the bulk of data gathered by their predecessors.
Innovation in biosimilars can also be seen in the routes of administration for biologics patients-e.g. switching formulation from I.V. to S.C.. Just by making delivery simpler, faster and more cost effective it will have significant impact for health care providers and convince for the patients.