What Regulators Want

Head to head

The Chemistry, Manufacturing and Control (CMC) dossier is an essential part of the submission package for any pharmaceutical product to enter a clinical trial and, in a later stage, for an application for market authorization. For a biosimilar, the CMC part is even more important and the core of a biosimilar’s dossier is a comprehensive head-to-head comparison of the biosimilar and the originator product, including points of difference between the two products, and how these will affect the product. The dossier must also include all details of the analytical (and other) methods that have been used to identify these differences (allowing the assessor at the regulatory agency to decide just how similar the two products actually are), as well as manufacturing details (including cell lines and sources of material), a description of the process control methods used, and information about how analytical data have been validated.

This head-to-head comparison is often made more difficult as data are rarely available for the originator products, which, in any case, may have changed through authorized manufacturing changes. In some cases, entire analytical exercises must be performed multiple times on different batches to enable comparisons to be made.

A comprehensive set of preclinical safety studies must also be carried out before any human volunteers or patients are dosed with the potential biosimilar, including in vitro assays and appropriate animal models, which are designed to predict whether those small differences may have an impact on safety or efficacy. Immunogenicity is a particular concern, but both in silico tools and in vitro assessments using animal tissue can be used to predict whether it is likely to occur in humans. Some regulations require animal immunogenicity studies be carried out before humans are dosed for the first time.

Clinical studies

For an originator product, phase I studies are typically carried out on somewhere between 30 and 48 healthy volunteers to establish safety; however, a biosimilar phase I study will involve anywhere between 120 and 200 healthy volunteers dosed with either the originator or the biosimilar drug. The trial will aim to detect differences in safety signals between the biosimilar and the originator product – and you need more participants to ensure the statistical relevance of results.

Study design should be agreed with the relevant regulatory authority to establish its acceptability and whether, based on the CMC dossier, the product may be considered biologically similar to the originator. Without this agreement, there is little point in continuing with development as it will be unlikely to gain marketing authorization via the biosimilar pathway. In addition to the phase I comparative safety study, a phase III study to prove equivalent efficacy is essential and the design of this study should be carefully coordinated with regulators to establish the necessary endpoints.

A biosimilar must have the same route of administration as the reference product and any changes to strength, pharmaceutical form or formulation, for example, will need to be justified to the regulators. Other changes, for example, optimizing the glycosylation pattern of the drug to improve efficacy, will not be compatible with biosimilarity. However, changes designed to improve safety, for example, reducing levels of known impurities or reducing immunogenicity, may not preclude a biosimilar decision.