Safety considerations
BioPharm: What are the safety issues that must be considered when developing a biosimilar product?
Quintiles: The most significant concern, from a safety perspective, with biosimilar medicines, is the risk of eliciting an inappropriate immunogenic response. It is difficult to predict, based on in-vitro characterizationalone, whether a biosimilar product will be more or less immunogenic than the originator molecule. In-vivo studies in animal models are also not particularly useful for determining immunogenicity of a protein in humans. This is especially so for recombinant human proteins, or ‘humanized’ antibodies (antibodies that have a significant part of their protein amino-acid sequence from human origin), as they are highly immunogenic in most animal models. For this reason also, animal models are not particularly useful in determining pharmacokinetics of biosimilar medicines because the immune response they stimulate accelerates their clearance from the animal.
Pharmacokinetic profile and safety testing of a biosimilar medicine, with the knowledge that this product has been well-characterized and determined to be highly similar to the originator medicine, needs to be conducted in humans. As a starting point to these studies, it should be understood that most biological medicines will lead to an immunogenic response in some patients. Immunogenicity rates of between less than 1% to more than 20% have been reported for human proteins and humanized therapeutic monoclonal antibodies (2). Therefore, clinical studies need to be designed to show, not only the similarity in efficacy of the biosimilar medicine to the originator, but also its immunological profile. This assessment is done by ensuring adequate patient exposure to the biosimilar medicine beyond the initial efficacy testing phase.
Defining biosimilarity
BioPharm: How do you define ‘similar’ when comparing a biosimilar with a reference product, given there will be differences caused by the manufacturing process?
NIBRT: The definition of similarity is complicated by nature of the fact that biologic products are expressed in living expression systems and differences regarding the manufacturing processes, be it cell lines used, media used, differences in downstream processing or processing between the innovator and the biosimilar process will undoubtedly exist. Furthermore, there is currently a lack of appropriate reference standardmaterial for the development of analytical methods for the evaluation of comparability and similarity. While batches of drug product are often used, it should be considered that the formulation of the drug product may interfere in the subsequent comparability/similarity study and attempts to deformulate the drug product may unknowingly introduce modifications into the molecule, which complicates the study from the offset. It is inappropriate to say that two molecules are identical due to the inherent complexity of the manufacturing process. Indeed, it has been demonstrated that measureable differences exist between different lots of an innovator product (3). The terms comparable, similar, and highly similar require definition by the regulatory authorities. Analytical chemistry generates the data that forms or backs up the argument regarding comparability or similarity; however, it will always be the decision of the regulators as to whether they believe the data are sufficient to justify such claims.
References
1. F. Nimmerjahn and J.V. Ravetch, Nat Rev Immunol 8 (1) 34-47 (2008).
2. FDA, “Prescribing Information,” www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm, accessed Aug. 10, 2013.
3. M. Schiestl et al., Nat Biotechnol, 29 (4) 310-312 (2011).