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

Publisher Copyright: © 2022, The Author(s).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.Peer reviewe

An exercise in transformational programming: Backtracking and Branch-and-Bound

We present a formal derivation of program schemes that are usually called Backtracking programs and Branch-and-Bound programs. The derivation consists of a series of transformation steps, specifically algebraic manipulations, on the initial specification until the desired programs are obtained. The well-known notions of linear recursion and tail recursion are extended, for structures, to elementwise linear recursion and elementwise tail recursion; and a transformation between them is derived too

中性子二次元検出器の開発と単結晶構造解析への応用

Tohoku University佐藤卓論

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms. Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.Peer reviewe

On Building Distributed Soft Real-Time Systems

When building a distributed real-time system, one can either build the whole system from scratch, or from pre-existing standard components. Although the former allows better scheduling design, it may not be economical in terms of the cost and time of development. This paper studies the performance of distributed soft real-time systems that use standard components with various scheduling algorithms and suggests ways to improve them.published_or_final_versio