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Biobetters Need a Definition!

The Biosimilars Clinical Studies & Analytical Similarity Summit held in Boston from March 21-23, 2016 covered a broad range of topics ranging from assay considerations to clinical study design and regulatory filing strategies. One topic that came up in virtually every presentation or discussion forum was the concept of “biobetters”. There is no formal definition of the term “biobetter” in either the FDA or EMA guidance or regulations for biosimilars. Various groups in the biopharmaceutical industry have crafted their own definitions of what would constitute a biobetter, and there is very little agreement across these proposed definitions. The range of elements proposed, which could make a biosimilar into a biobetter included:

· Changes to drug product formulation to improve stability

· Changing the administration route to improve patient acceptance or ease of use

· Improvement to the glyco-profile or sialylation

Some of the elements proposed would still “fit” into the existing biosimilar filing pathways. For example, changes in amounts of excipients, or switching to another commonly used excipient (e.g., substituting citrate for phosphate as the buffering salt) would generally be allowed as long as pharmacokinetic behavior was comparable. However, using a novel excipient would not be allowed under the EMA biosimilar filing pathway.

Changes to protein isoform distribution is another area where non-impactful changes could be allowed. For instance, if the biosimilar sponsor can demonstrate there is no potency or pharmacokinetic behavioral difference in a molecule with ½ the deamidation present in the innovator molecule, this change would generally not preclude a biosimilar filing pathway. The “totality of evidence” must be in favor of the molecule being considered highly similar to the innovator with no clinically relevant differences.

However, if a sponsor proposed filing a biosimilar application for a molecule with increased sialylation – and consequently a measureable difference in pharmacokinetic behavior, the EMA could not accept the filing according to the requirements of the biosimilar regulations. The difference in pharmacokinetic behavior cannot be compensated for by simply adjusting dose level, the molecule would not be considered a biosimilar because patient exposure is not comparable. There would be at least a theoretical advantage in being able to reduce dosing of a biopharmaceutical while maintaining therapeutic effect, so this situation could be viewed as an unintended negative outcome of the regulation, and should be further discussed in an appropriate forum.

By the end of the conference, it was very clear that the concept of “deliberate biobetters” does not fit into the current biosimilar regulatory pathways. The proper approval mechanism for a molecule, which demonstrates greater potency, better pharmacokinetic behavior, or other clinically relevant differences, is the standard new molecular entity approval pathway. Clearly, the definition of what constitutes a “biobetter” is a topic that requires discussion in an appropriate forum.

 

Blog article by: Joe Siemiatkoski