The importance of World Health Organization international reference standards in the product life cycle of biosimilars.

Technological advances in analytics, as well as scientific and regulatory knowledge and experience gained from biosimilar development/approvals over the last decade, enabled the World Health Organization (WHO) in 2022 to revise its guidelines on the evaluation of biosimilars. Among the revisions, there is more reliance on analytical and functional aspects to prove similarity (and likely fewer clinical requirements). WHO international reference standards for biosimilars provide additional confidence to regulators looking for evidence- and data-based regulatory convergence in scientific and technical measures of quality attributes.

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

The World Health Assembly resolution on access to biotherapeutics in 2014 urges WHO and Member States to facilitate access to biotherapeutics while ensuring their quality, safety, and efficacy. While efforts to date have contributed to increased availability and better access to biotherapeutics, including biosimilars, huge gaps still remain, with lack of product access identified as a problem in many countries. A thorough review of the WHO guidelines on biosimilars issued in 2009 in view of technical developments, accumulated and emerging scientific evidence as well as experience in biosimilar evaluation since the release of the guidelines provided an opportunity to introduce greater flexibility and to reduce regulatory requirements in biosimilar development where possible.

Interaction effect between NAFLD severity and high carbohydrate diet on gut microbiome alteration and hepatic lipogenesis.

Nonalcoholic fatty liver disease (NAFLD) is associated with high carbohydrate (HC) intake. We investigated whether the relationship between carbohydrate intake and NAFLD is mediated by interactions between gut microbial modulation, impaired insulin response, and hepatic lipogenesis (DNL). Stool samples were collected from 204 Korean subjects with biopsy-proven NAFLD (n = 129) and without NAFLD (n = 75).

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

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.

WHO informal consultation on revision of guidelines on evaluation of similar biotherapeutic products, virtual meeting, 30 June - 2 July 2021.

The WHO informal consultation was held to promote the revision of WHO guidelines on evaluation of similar biotherapeutic products (SBPs) adopted by the Expert Committee on Biological Standardization (ECBS) in 2009. It was agreed in the past consultations that the evaluation principles in the guidelines are still valid, but a review was recommended to provide more clarity and case-by-case flexibility. The opportunity was therefore taken to review the experience and identify areas where the current guidance could be more permissive without compromising its basic principles, and where additional explanation could be provided regarding the possibility of reducing the amount of data needed for regulatory approval.

Activation of ectopic olfactory receptor 544 induces GLP-1 secretion and regulates gut inflammation.

Olfactory receptors are ectopically expressed in extra-nasal tissues. The gut is constantly exposed to high levels of odorants where ectopic olfactory receptors may play critical roles. Activation of ectopic olfactory receptor 544 (Olfr544) by azelaic acid (AzA), an Olfr544 ligand, reduces adiposity in mice fed a high-fat diet (HFD) by regulating fuel preference to fats.

Development of mRNA Vaccines: Scientific and Regulatory Issues.

The global research and development of mRNA vaccines have been prodigious over the past decade, and the work in this field has been stimulated by the urgent need for rapid development of vaccines in response to an emergent disease such as the current COVID-19 pandemic. Nevertheless, there remain gaps in our understanding of the mechanism of action of mRNA vaccines, as well as their long-term performance in areas such as safety and efficacy. This paper reviews the technologies and processes used for developing mRNA prophylactic vaccines, the current status of vaccine development, and discusses the immune responses induced by mRNA vaccines.

Regulatory challenges with biosimilars: an update from 20 countries.

The World Health Organization (WHO) issued guidelines for the regulatory evaluation of biosimilars in 2009 and has provided considerable effort toward helping member states implement the evaluation principles in the guidelines into their regulatory practices. Despite this effort, a recent WHO survey (conducted in 2019-2020) has revealed four main remaining challenges: unavailable/insufficient reference products in the country; lack of resources; problems with the quality of some biosimilars (and even more with noninnovator products); and difficulties with the practice of interchangeability and naming of biosimilars. The following have been identified as opportunities/solutions for regulatory authorities to deal with the existing challenges: (1) exchange of information on products with other regulatory authorities and accepting foreign licensed and sourced reference products, hence avoiding conducting unnecessary (duplicate) bridging studies; (2) use of a "reliance" concept and/or joint review for the assessment and approval of biosimilars; (3) review and reassessment of the products already approved before the establishment of a regulatory framework for biosimilar approval; and (4) setting appropriate regulatory oversight for good pharmacovigilance, which is essential for the identification of problems with products and establishing the safety and efficacy of interchangeability of biosimilars.

Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in non-obese individuals. Gut microbiome profiles of 171 Asians with biopsy-proven NAFLD and 31 non-NAFLD controls are analyzed using 16S rRNA sequencing; an independent Western cohort is used for external validation. Subjects are classified into three subgroups according to histological spectra of NAFLD or fibrosis severity.

WHO informal consultation on the guidelines for evaluation of the quality, safety, and efficacy of DNA vaccines, Geneva, Switzerland, December 2019.

Consultations have been held to promote the revision of the WHO guidelines for assuring the quality and nonclinical safety evaluation of DNA vaccines adopted by the Expert Committee on Biological Standardization (ECBS) in 2005. The drivers for this revision are described, including the need for regulatory convergence highlighted by the WHO R&D Blueprint. These consultations have driven the revision to its current form, where a new guideline that includes quality, nonclinical, and clinical evaluation of plasmid DNA vaccines is being prepared for public consultation with a view to present to an upcoming ECBS.

Removal of the innocuity test from The International Pharmacopoeia and WHO recommendations for vaccines and biological products.

The innocuity test was indicated as a quality control test to release pharmaceutical and biological products to the market. The test was intended to detect possible extraneous toxic contaminants derived from the manufacturing processes of the product. The test was included in WHO Recommendations and Guidelines for vaccines, biotherapeutics and blood products and in some monographs on antibiotics in The International Pharmacopoeia.

The regulatory landscape of biosimilars: WHO efforts and progress made from 2009 to 2019.

The World Health Assembly in 2014 adopted a resolution that mandates both Member States and the WHO Secretariat to facilitate access to biotherapeutic products in a way that ensures their quality, safety and efficacy. The availability of biosimilars is expected to increase access to biotherapeutic products by providing more treatment options triggering competition which would lead to a consistent reduction in the average price of treatment. Since the WHO guidelines for regulatory evaluation of biosimilars were issued in 2009, WHO has provided immense effort towards harmonizing the terminology and the regulatory framework for biosimilars globally.

WHO implementation workshop on guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 25-26 June 2019.

The first global workshop on implementation of the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products adopted by the WHO Expert Committee in 2018 was held in June 2019. The workshop participants recognized that the principles based on sound science and the potential for risk, as described in the WHO Guidelines on post-approval changes, which constitute the global standard for product life-cycle management are providing clarity and helping national regulatory authorities in establishing guidance while improving time-lines for an efficient regulation of products. Consequently, the regulatory situation for post-approval changes and guideline implementation is changing but there is a disparity between different countries.

Quality assessment and its impact on clinical performance of a biosimilar erythropoietin: A simulated case study.

The case study described in this paper was developed for the purpose of training for a better understanding of principles relating especially to a comprehensive evaluation of multiple quality attributes as outlined in the WHO guidelines on evaluation of similar biotherapeutic products. It is also to emphasize the importance of an understanding of the critical quality attributes and a risk assessment of the impact on clinical performance. It was prepared to mimic a real situation in which regulators need to evaluate the differences in quality attributes known to have potential impact on clinical activity.

Quality changes to approved biotherapeutic product: Simulated case studies on reporting categories & supporting data requirements.

Changes are essential for the continual improvement of the manufacturing process and for maintaining state-of-the-art controls on biotherapeutic products and such changes often need to be implemented after the product has been approved. WHO guidelines on procedures and data requirement for changes to approved biotherapeutic products were issued in 2017 to provide guidance to national regulatory authorities and manufacturers on the regulation of changes to already licensed biotherapeutic products in order to assure their continued quality, safety and efficacy, as well as continuity of supply and access. The case studies in this article were prepared to be used for WHO implementation workshops.

Early life determinants induce sustainable changes in the gut microbiome of six-year-old children.

While the association between early life determinants and the development of the gut microbiome composition in infancy has been widely investigated, a potential persistent influence of early life determinants on the gut microbial community after its stabilization at later childhood remains largely unknown. Therefore, we aimed to identify the association between several early life determinants and the gut microbiome composition in six-year-old children from the LISA birth cohort. A total number of 166 fecal samples were analyzed using 16S rRNA gene-based barcoding to assess bacterial diversity pattern.

Regulatory evaluation of biosimilars throughout their product life-cycle.

The World Health Assembly in 2014 adopted a resolution that recognized the importance of increasing access to biotherapeutic products, of improving their affordability and of ensuring their quality, safety and efficacy. Biosimilars are biotherapeutic products similar to already licensed reference products and are usually developed after patents on the original products have expired. Their introduction into the market is likely to reduce the costs of medicines substantially, thereby improving the availability of treatment for patients.

WHO informal consultation on development of guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 27-28 April 2017.

In April 2017, WHO convened an informal consultation to develop WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products. The objective of the meeting was to review the draft of WHO guidelines and the comments received from the public consultation. The guidelines were recognized by the participants as a tool for regulatory convergence and harmonization.

Immunogenicity assessment of monoclonal antibody products: A simulated case study correlating antibody induction with clinical outcomes.

Monoclonal antibodies are large molecules with complex structure and functions. They have a wide application for treatment of a broad range of chronic diseases and represent the largest class of biotherapeutic products. Given that biotherapeutic products may induce unwanted humoral and/or cellular immune responses in recipients, it is essential to investigate the immunogenicity of a product prior to licensure.

Implementation workshop of WHO guidelines on evaluation of malaria vaccines: Current regulatory concepts and issues related to vaccine quality, Pretoria, South Africa 07 Nov 2014.

The current World Health Organization (WHO) guidelines on the quality, safety and efficacy of recombinant malaria vaccines targeting the pre-erythrocytic and blood stages of Plasmodium falciparum were adopted by the WHO Expert Committee on Biological Standardization in 2012 to provide guidance on the quality, nonclinical and clinical aspects of recombinant malaria vaccines. A WHO workshop was organised to facilitate implementation into African (national/regional) regulatory practices, of the regulatory evaluation principles outlined in the guidelines regarding quality aspects. The workshop was used also to share knowledge and experience on regulatory topics of chemistry, manufacturing and control with a focus on vaccines through presentations and an interactive discussion using a case study approach.

Immunogenicity assessment of biotherapeutic products: An overview of assays and their utility.

Biotherapeutic products (BTPs) are the fastest growing medicines in the pharmaceutical market. Despite their clinical success, the immunogenicity of BTPs continues to be a major concern. Assessment of immunogenicity as well as appropriate interpretation of immunogenicity data is therefore, of critical importance for defining safety profile of these products for the purpose of their licensure and use.

Review of the current use and evaluation of cell substrates for producing biologicals in selected countries.

In 2010, the WHO guidance document for the evaluation of cell substrates for producing biologicals was replaced with updated recommendations and in May 2013 an implementation workshop on the new recommendations was held in Beijing, China. As part of this workshop, a survey of the use and evaluation of cell substrates for producing biologicals was undertaken and the information obtained was updated in June 2014. The purpose of survey was to capture the status of national requirements related to cell substrates in various countries with particular emphasis on whether or not the updated WHO recommendations had been, or were to be, incorporated into national requirements.

Case studies on clinical evaluation of biosimilar monoclonal antibody: scientific considerations for regulatory approval.

The objective of this paper is to provide considerations based on comprehensive case studies important for regulatory evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs) with a special emphasis on clinical aspects. Scientific principles from WHO Guidelines on SBPs were used as a basis for the exercise. Working groups consisted of regulators, manufacturers and academia.