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. In the past decade, much progress has been made towards how immunogenicity should be studied. This article reflects the content of the brief presentation on principles of methods used for immunogenicity assessment and their merits and limitations given at the first World Health Organization (WHO) implementation workshop on rDNA derived biotherapeutic products held in the Republic of Korea in May 2014 to support the case studies on immunogenicity presented and discussed during the workshop. The purpose of this article is to provide an overview of the methods used for assessing immunogenicity of biotherapeutic products (BTPs) and the most important considerations in interpreting results in the context of regulatory overview of these products.
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. It also discusses important issues with regard to the evaluation of mRNA vaccines from regulatory perspectives. Setting global norms and standards for biologicals including vaccines to assure their quality, safety and efficacy has been a WHO mandate and a core function for more than 70 years. New initiatives are ongoing at WHO to arrive at a broad consensus to formulate international guidance on the manufacture and quality control, as well as nonclinical and clinical evaluation of mRNA vaccines, which is deemed necessary to facilitate international convergence of manufacturing and regulatory practices and provide support to National Regulatory Authorities in WHO member states.
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.
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. However, there are barriers to market access for biosimilars. This article discusses the factors that give rise to these barriers and explains the importance of regulatory oversight throughout the product life-cycle of biosimilars. The paper also describes the role regulators can play in increasing confidence in biosimilars use by: (i) establishing regulatory oversight of biosimilars throughout their life-cycle, from development to post-licensing oversight, and ensuring that only high-quality, safe and efficacious biosimilars are available on the market; (ii) ensuring regulatory authorities have adequate capacity to assess and monitor the quality, safety and efficacy of biosimilars throughout their life-cycle; and (iii) monitoring the use of biosimilars in public health systems in collaboration with other stakeholders.
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