Bioequivalence and biosimilars

Profil has extensive experience in bioequivalence trials with both healthy subjects and patients with diabetes mellitus. We can fully support trial and data analysis optimization and help obtain scientific advice from regulatory authorities in Europe and the U.S.  

Biosimilar medicines have the same molecular structure as a marketing reference product and display similar physicochemical properties. However, unlike small molecule drugs and their generic copies, which are usually identical and reproducible, the complex manufacturing process for proteins leads to structural differences (e.g., changes in glycosylation patterns) between a biosimilar and a reference product.

Thus, insulin biosimilars are not identical to their reference products, and the differences could affect the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles. Therefore, well-designed clinical bioequivalence studies (or biosimilar studies) are important to demonstrate the biosimilar nature of a test product.

The development programs for biosimilar drugs are highly regulated by authorities. For insulin biosimilars, specific guidelines were developed by the EMA (final version published in February 2015). They give recommendations for the clinical trial design (e.g., double-blind, cross-over, single dose), choice of study population (healthy volunteers vs. patients with type 1 diabetes) and the required statistical analysis. The guidelines clearly suggest primary and secondary PK and PD endpoints and request the demonstration of both PK and PD bioequivalence.

However, PD parameters often are more variable than PK parameters, and demonstration of PD bioequivalence can be quite difficult. Studies with huge sample sizes may be required. It is therefore essential to know the exact regulatory requirements and to optimize the design of bioequivalence studies for each individual insulin formulation after consulting regulatory guidelines and even the regulatory authorities.