In a recent article, we discussed the changes that the FDA announced regarding the removal of the requirement for clinical efficacy studies (CES) for monoclonal antibodies. This laudable decision was the result of the recognition that CES do not provide value in terms of generating meaningful data as part of a biosimilar development program. This change places the emphasis of biosimilarity demonstration squarely on the shoulders of the analytics, which is a fact clearly recognized and acknowledged by the FDA. Undoubtedly, techniques and technologies for analytical assessment of biosimilarity are sensitive and discriminatory in terms of the recognition of differences in structure. They are certainly up to the task of providing meaningful data for conclusions of biosimilarity when appropriately applied, as defined in the biosimilar guidelines published by numerous regulatory authorities.
In a further recent development, the FDA has now published draft guidance on the need for CES across the entirety of biosimilar products (1). This guidance now removes the necessity for CES across all products being developed as biosimilars within the jurisdiction of the FDA. This move is a very rapid development following on from the FDA’s recent mAb product-only position. It makes sense for the FDA to take this much broader stance following the partial erosion of their CES requirements within the biosimilar field. It would not be tenable to support a position where mAbs were excluded from the necessity of CES, but other biosimilars were not. The FDA’s position now fully aligns with the UK MHRA’s position on CES for biosimilars (2).
This now very clearly demonstrates the recognition that state-of-the-art analytical technologies are sufficiently sensitive and discriminatory in their ability to detect differences between innovator and proposed biosimilar, not only for mAbs but for other products as well. This includes products that will have very different structural components from mAbs, such as more complex glycosylation, a challenging disulfide bridge pattern, or the presence of other post-translational modifications. Analytical data generated must be able to identify structures that may be cause for concern. For example, those that have the potential to be immunogenic, such as the Galα1-3Gal glycan epitope. The presence of these structures may then trigger a redevelopment of the product or, depending on the position of the manufacturer and FDA, may lead to the requirement to perform CES.
Understand how regulatory expectations shape biosimilar testing - from primary sequence confirmation to advanced comparability analysis. This blog explains the structural and physico-chemical assays your biosimilar must undergo.
Structural analysis and the application of state-of-the-art technologies and techniques must now be clearly recognized as the vanguard of comparability assessments for biosimilar products. The detailed structural characterizations required by regulatory agencies, referencing ICH Q6B guidance (3), take on new meaning when they are now the decisive factors on which claims of biosimilarity may stand or fall. Analytical investigations and scrutiny of data are needed at all stages of biosimilar development to determine that the product is fit to be labelled as a biosimilar and that the manufacturing process can be repeated to support that biosimilarity claim.
So where do we go from here? With the FDA and MHRA now both removing the necessity of clinical trials from their biosimilar pathways and the EMA actively looking at this (4) it seems that it is only a matter of time before we will have a new and very welcome global paradigm for biosimilars. It is a testament to the strength and application of analytical technologies, where we can now show that analyses alone have provided reliable evidence for biosimilarity claims over the years. These analyses, along with relevant biological characterization and PK studies, can be relied on as the means of demonstrating biosimilarity going forward. This dramatically cuts costs for developing biosimilars and thus delivers more affordable treatments to patients where agencies have adopted this position. It is likely this will soon become the global norm.
With clinical efficacy studies no longer required for biosimilar products in the US, expert analytical support is more important than ever. Speak directly with a BioPharmaSpec scientist to ensure your characterization data meets the new FDA expectations.
