11^th European Biosimilars Congress

The prevailing view is that the structure of biosimilars cannot be established or even manufactured to be identical to the original product. This residual uncertainty needs to be addressed by bridging clinical data, which generally includes a PK (pharmacokinetic) and a therapeutic equivalence trial. However, very limited consideration has been given to what this residual uncertainty is and the extent to which such trials could be suitable or are necessary to address this perceived uncertainty. While it is true that structural differences are possible between the reference product and the biosimilar and that such differences may impact PK, potency, immunogenicity and safety, the generally proscribed clinical trial program may not always be the appropriate approach to discerning the impact of such differences. In fact such structural changes have also been observed to occur due to process changes introduced in the manufacture of the reference product with no requirement for supporting clinical data. Looking at this objectively, PK can usually be effectively addressed in clinical trials often in healthy subjects; in most cases these are relatively straight forward trials to perform and provide clear evidence for PK equivalence. Potency on the other hand is generally required to be studied in therapeutic trials but the value of such trials is debatable. Often the therapeutic dose may lie on the flat part of the dose response curve so that even if a difference in potency existed it would not be detected whereas in vitro methods are far more sensitive to detect differences. There are also considerable challenges in designing and executing therapeutic equivalence trials whereas in fact it is immunogenicity and safety where residual uncertainty remains, and which needs to be addressed in clinical trials.