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Foreword: Biosimilars – future prospects

30 June 2016  •  Author(s): Dave P. Elder, JPAG chair and Consultant

David ElderBiologically-derived drugs, such as proteins, peptides and monoclonal antibodies (mABs), are playing an increasingly important role in global healthcare. It was recently reported that mAB therapeutics sell for over $50 billion1 globally. However, one of the major downsides of biological therapeutics is their significantly greater costs compared with small molecule drugs, which puts an increased burden on global health services.

Biosimilars should, in theory, provide a lower cost alternative to the more expensive innovator drugs. However, there are several impediments to biosimilar approval. Determination of therapeutic equivalence based on demonstrating bioequivalence (equivalent pharmacokinetic parameters of test and reference compound) is the cornerstone of small molecule generic regulatory approval, but this approach cannot be used for biologicals. The main reason is that due to the chemical and physical complexity of biologicals, including differences in conformational structure and post-translational modifications, bioequivalence testing, whilst demonstrating similar efficacy, cannot fully show that the test and reference compounds will have similar safety profiles2 . Biosimilars cannot, therefore, be viewed as true generics. Instead they exhibit a high level of similarity to the reference product and can be considered to be both biologically and clinically similar to the innovator product. Therefore, the development process for biosimilars is significantly more complex than for a true ‘generic’2.

The United States Food and Drug Administration3 and the European Medicines Agency (EMA)4 both provide guidance for the development of biosimilar drugs. Biological manufacturers typically ‘lock-down’ the manufacturing process as early as possible before pivotal clinical studies. However, this approach is challenging and ICH Q5E5 provides ‘comparability’ guidance as part of a change control mechanism. ICH Q5E highlights that the primary goal of a comparability exercise is to provide assurance of quality, safety and efficacy of a biological product produced when there are changes in a manufacturing process. This guidance further highlights that there are no requirements for identical quality attributes, but that they should be highly similar. However, these differences should have no adverse impact on either safety or efficacy. The comparability protocol can be based on a combination of both analytical and biological assays, as well as both non-clinical and, if required, clinical data. Clinical testing may be required if there is no defined relationship between specified quality attributes and safety and efficacy end points…

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