A study carried out by Kurki P et al. in 2022 reviewed the current clinical experience and scientific evidence to provide an expert perspective for updating the World Health Organization (WHO) guidelines on evaluation of similar biotherapeutic products (SBPs; also called biosimilars) to increase flexibility and clarity.
The original WHO guidelines were adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2009. In 2019, the Committee considered that a more tailored and potentially reduced clinical data package may be acceptable in cases where this was clearly supported by the available scientific evidence.
Firstly, the authors reviewed relevant newer guidelines issued by other regulatory bodies to identify issues that might help updating the WHO guidelines. This review suggested that the WHO guidelines may need more emphasis on the importance of the state-of-the-art physicochemical and structural comparability exercise and in vitro functional testing. In contrast, current non-clinical in vivo toxicological tests are not useful in the development of biosimilars. The use of ‘foreign’ reference product will also need clarifications. The concepts of ‘totality of evidence’ and ‘residual uncertainty’ are still relevant for the development of biosimilars .
Secondly, a literature search was conducted for long-term efficacy, safety, and immunogenicity of biosimilars to identify possible long-term problems that some stakeholders anticipated at the time of licensing. The study review confirmed the robustness of the current biosimilar development concept. Thus, the initially perceived residual uncertainty regarding safety, immunogenicity, and efficacy of biosimilars that shaped the original regulatory guidelines is now substantially reduced.
Finally, a search for articles concerning the role of clinical studies in the benefit-risk evaluation of biosimilars was conducted. The analyses of the roles of different development phases suggested that the large confirmatory efficacy, safety, and immunogenicity studies are, in most cases, redundant.
The authors concluded that current data suggest that state-of-the-art analytical and functional testing and robust head-to-head pharmacokinetic and/or pharmacodynamic studies are sufficient to demonstrate biosimilarity in most cases. In vivo animal studies and large confirmatory efficacy and safety studies should be considered only on a case-by-case basis .
The review provided an opportunity to identify areas where the current guidance could be more permissive without compromising safety and efficacy. Consequently, WHO guidelines for biosimilars were revised and the ECBS adopted the revision in April 2022 .
From public health perspective, this is considered as an important step towards a better access to biotherapeutic products and a contribution to the implementation of the World Health Assembly Resolution WHA67.21 on access to biotherapeutic products including similar biotherapeutic and ensuring their quality, safety, and efficacy.
Back in early 2019, the WHO’s Regulation of Medicines and other Health Technologies (RHT) Department detailed a Q&A document, which is an additional guidance that complements the existing guidelines and deals with a number of issues regarding licensing SBPs, reference biological products, quality, non-clinical and clinical evaluation and pharmacovigilance .
Conflict of interest
This research paper  was funded by Ministry of Health and Welfare of the Republic of Korea; and the open access of the research paper  is also supported by the Norwegian Agency for Development Co-operation. For full details of the authors’ conflict of interest, see the research paper .
The authors of the research paper  declared that there was no conflict of interest.
Abstracted by Adjunct Professor Pekka Kurki, MD, PhD, University of Helsinki, 19 Lukupolku, FI-00680 Helsinki, Finland.
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1. Kurki P, Kang H-N, Ekman N, et al. Regulatory evaluation of biosimilars: refinement of principles based on the scientific evidence and clinical experience. BioDrugs. 2022;36(3):359-71.
2. World Health Organization. Guidelines on evaluation of biosimilars. Replacement of Annex 2 of WHO Technical Report Series, No. 977 [homepage on the Internet]. [cited 2021 Jul 8]. Available from: https://cdn.who.int/media/docs/default-source/biologicals/bs-documents-(ecbs)/annex-3---who-guidelines-on-evaluation-of-biosimilars_22-apr-2022.pdf?sfvrsn=e127cbf4_1&download=true
3. GaBI Online - Generics and Biosimilars Initiative. WHO releases Q&A on biosimilars evaluation [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2022 Jul 8]. Available from: www.gabionline.net/reports/WHO-releases-Q-A-on-biosimilars-evaluation
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