Explaining biosimilars and how reverse engineering plays a critical role in their development

ABSTRACT

Introduction

Biologicals are protein-based therapeutics consisting of larger and more complex structures than small molecule medicines. As the patents for originator biological therapeutics expire, biosimilar products are licensed for the same indications as their marketed reference biologics across different specialities. Owing to the complex nature of the manufacturing process for a biological therapy compared to conventional chemically synthetized medicines, the development of biosimilars is more complicated and costly than the manufacture of generic small molecules.

Areas covered

The manufacturing process of the originator biologic is in most cases largely unknown to biosimilar developers and therefore reverse engineering through extensive analysis of the originator is a fundamental and critical step for successful biosimilar development. In this review, the authors examine the abbreviated roadmap for biosimilar approval which must be underpinned by the same rigorous standards that apply to all biological medicines. They discuss various aspects of biosimilar manufacturing with a focus on reverse engineering.

Expert opinion

The biosimilar approval pathway places a greater emphasis on preclinical assessments in comparison to the development of originator biologics. Multiple comparative clinical studies add little to the confirmation of the efficacy of the molecule under study whilst adding considerably to the cost and time of bringing a biosimilar into clinical use. A successful demonstration of biosimilarity to the reference product is therefore essential at a structural and functional level but this could not be achieved without well-designed and quality-driven reverse engineering of the originator production process.

KEYWORDS:

• Biosimilars
• reverse engineering
• biologicals
• biosimilarity

Article highlights

• The manufacturing process of the originator biologic is in most cases unknown to biosimilar developers: reverse engineering through extensive analysis of the originator is, therefore, a critical step in biosimilar development.

• The approach to the manufacture of biosimilars has been ameliorated over the last years through the implementation of quality by design (QbD) methodologies focusing the attention on the importance of investing time and resources upfront in their development.

• A confirmatory clinical trial of the biosimilar candidate may not be necessary if efficacy and safety can be clearly deduced from the preclinical similarity exercise as clinical validation actually adds little in terms of confirming the efficacy of the molecule.

• The wider acceptance of extrapolation as a scientific other than a regulatory principle can be considered a direct result of the robustness of preclinical data.

• A successful demonstration of biosimilarity at a structural and functional level is essential and not achievable without well-designed and quality-driven reverse engineering of the production process

This box summarizes key points contained in the article.

Declaration of interest

CJ Edwards has received honoraria for advisory board participation and for speaker’s bureau participation and has received research support from AbbVie, Bristol-Myers Squibb, Biogen Idec, Celgene, Celltrion, Fresenius, Gilead Biosciences, Janssen Pharmaceuticals, Eli Lilly and Company, MundiPharma, Pfizer Inc, Merck Sharp and Dohme, Novartis, Roche, Samsung, Sanofi and UCB Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.