At the recent Biosimilars Summit in Philadelphia, Cytel's Pantelis Vlachos presented on statistical challenges and flexible approaches in biosimilar development. In this blog we summarize some of the challenges and share the slides from talk.
In summary, a biosimilar product is a biological product that is approved based on demonstrating high similarity to an FDA approved biological product (or reference product). It should demonstrate no clinically meaningful differences in terms of safety and effectiveness from the reference product and only minor differences in clinically inactive components are allowable in biosimilar products (FDA).
In biosimilar development Phase 1 studies serve as pivotal trials in a two-step process which consists of Phase 1 studies to demonstrate similar Pharmacokinetic (PK) and Phamacodynamic ( PD ) effect, and Phase 3 to explore efficacy and provide further safety evaluation.
Typically, in a Phase 1 biosimilar study there are issues with variability. Further, there is a lack of knowledge about the nature of the variability, producing uncertainties in the optimal design since traditionally, all key design parameters are fixed until completion. Historically, Phase 1 bioequvialence studies consisted of a simple repetition of the original trial (without α-adjustment),. Known as 'add-on' trials these are no longer permitted by most regulatory agencies. The other 'traditional' approach consisted of a 'real' pilot trial which aimed to estimate treatment effect and co-efficient of variation ( CV) combined with a pivotal trial. However, this approach often performs sub-optimally.
In fact, flexible strategies including group sequential designs as well as unblinded and blinded Sample Size Re-estimation approaches may be used in this setting, and in certain cases may help to resolve some of the challenges. However, as with non-biosimilar trials, proper justification for any adaptive approach needs to be provided to the regulators. Working with a statistics group with strong regulatory interaction experience is critical.
In Phase 3 biosimilar trials, robust statistical approaches can address key challenges such as handling of missing values and identification of most sensitive population.
To download Vlachos slides from the conference click the button below.
Pantelis Vlachos is Director Strategic Consulting at Cytel. His research interests lie in the area of adaptive designs, mainly from a Bayesian perspective, as well as hierarchical model testing and checking. He was a founding member and the Managing Editor of the journal “Bayesian Analysis” and has served in the editorial boards of several other journals and online statistical data and software archives.