Regulatory Evaluation of Biosimilars: Refinement of Principles Based on the Scientific Evidence and Clinical Experience

Abstract

The World Health Organization (WHO) guidelines on evaluation of similar biotherapeutic products (SBPs; also called biosimilars) were adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2009. In 2019, the ECBS 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. The goal of this publication is to review the current clinical experience and scientific evidence and to provide an expert perspective for updating the WHO guidelines to provide more flexibility and clarity. As the first step, the relevant guidelines by other regulatory bodies were reviewed in order to identify issues that might help with updating the WHO guidelines. Next, a literature search was conducted for information on the long-term efficacy, safety, and immunogenicity of biosimilars to identify possible long-term problems. Finally, a search for articles concerning the role of clinical studies in the benefit–risk evaluation of biosimilars was conducted. The analysis of other guidelines 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. The use of “foreign” reference product will also need clarifications. The value of in vivo toxicological tests in the development of biosimilars is questionable, and the non-clinical part needs revisions accordingly. The concepts of “totality of evidence,” “stepwise development,” and “residual uncertainty” were applied in the evaluation of the clinical sections of the guideline. The review of long-term safety and efficacy demonstrated the robustness of the current biosimilar development concept. The analysis of the roles of different development phases suggested that the large efficacy, safety, and immunogenicity studies are, in most cases, redundant. The residual uncertainty of safety, immunogenicity, and efficacy of biosimilars that has shaped the current regulatory guidelines is now substantially reduced. This will allow the re-evaluation of the non-clinical and clinical requirements of the current WHO main guideline. The shift of the relative impact of the development phases towards physico-chemical and in vitro functional testing will provide a relief to the manufacturers and new challenges to the regulators.

Switching from One Biosimilar to Another Biosimilar of the Same Reference Biologic: A Systematic Review of Studies

“…Indeed, it would not be practical to mandate such studies, and if such studies were conducted the sheer number of studies would strain regulatory resources. Further considering the value of randomized clinical trials in the development of biosimilars, evidence has accumulated that phase 3-style efficacy and safety studies rarely contribute pivotal data to the totality of data supporting initial approval [54][55][56]. Likewise, analysis of the data from the studies identified in this systematic review clearly reveals that meaningful data on biosimilar-to-biosimilar switching can be obtained without the need for RCTs.…”

WHO guidelines on biosimilars: Toward improved access to safe and effective products

“…This provided an opportunity to evaluate new developments, identify areas where the guidance could be more flexible without compromising the basic principles, and allow for the provision of additional explanation of the possibility of reducing the amount of data needed for regulatory approval. 6,7 The use of state-of-the-art methodologies in the characterization and in vitro functional testing of biosimilars and the understanding of quality attributes that may impact clinical performance provide the potential to reduce the clinical data requirements in biosimilar assessment. In response to the recommendation, work to revise the guidelines was initiated, and the final draft revision after extensive consultation involving several rounds of regulatory expert review and two rounds of public consultation was adopted by the WHO ECBS in April 2022.…”

Indian Biosimilars and Vaccines at Crossroads–Replicating the Success of Pharmagenerics

“…The next important factor is the complex regulatory environment and ethical issues, including intellectual property rights, cell/tissue banking, sample transfer regulations, toxicology (safety issues), product manufacturing regulations, approval process for the product before hitting the market, clinical trials, etc. [ 74 ].…”