Biologicals are derived from living cells and therefore demonstrate molecular complexity and heterogeneity. This makes them very difficult to reproduce, as even very small changes in the manufacturing process can cause variations in the final drug, even between different batches of the same product.

For this reason biosimilars must be ‘similar but not identical’ to its reference biological, and for this same reason EMA requires a very thorough comparison of the structural and functional characteristics, and the product and process-related impurities of the biosimilar and the reference biological. Any differences found then have to be explained and justified with regard to the potential impact on the clinical performance of the biosimilar.

Data requirements for the development and licensing of biosimilars are considerably greater than for small molecule generics. Generics typically only require physicochemical identification and demonstration of a similar pharmacokinetic profile (bioequivalence) to the originator product. Biosimilars, on the other hand, need a more extensive head-to-head comparison with the reference product, to ensure close resemblance in physicochemical and biological characteristics, safety and efficacy.

Although a repetition of the entire development programme of the reference biological is scientifically not necessary, and could even be considered unethical, the type and extent of clinical data required for biosimilars vary and depend on:

• The complexity of the active substance and how well it can be characterized
• The availability of an accepted surrogate end point to compare efficacy
• The type and seriousness of safety concerns that have been encountered with the reference product or the substance class
• The possibility to extrapolate efficacy and safety data to other indications of the reference biological

This and the two articles that follow focus on the issues involved in and the concerns that clinicians should consider when choosing biosimilars.

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Related articles

Efficacy, extrapolation and interchangeability of biosimilars

Quality, similarity and safety of biosimilars

Small molecule versus biological drugs

Reference

1.  Weise M, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-7.

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