Summary of the diverse situation of similar biotherapeutic products in the selected countries (August 2010)

AbstractThe WHO guidelines on evaluating similar biotherapeutic products (SBPs) were adopted by the Expert Committee on Biological Standardization in 2009. The fundamental messages of the guidelines are that a) generic approach is not suitable for licensing SBPs, b) only products that have been subjected to a comparability exercise and show similarity to the reference biotherapeutic product (RBP) in terms of their quality, safety and efficacy are defined as SBPs, and c) the products that are not shown to be similar to the originator products as indicated in the guidelines should neither be described as "similar" nor called SBPs. In view of these, the products which have not been subjected to a head to head comparison with the RBP should be referred to as another term, e.g. ‘non-innovator’ therapeutic products.In order to review the current situation in each country, a survey was planned in line with the implementation workshop of the guidelines in August 2010. The results show that the diversity of regulatory framework for licensing SBPs and the ambiguous use of the terms, ‘similar’ or ‘generic’, present considerable challenges for the future use of SBPs

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

Ginseng Protects Against Respiratory Syncytial Virus by Modulating Multiple Immune Cells and Inhibiting Viral Replication

Ginseng has been used in humans for thousands of years but its effects on viral infection have not been well understood. We investigated the effects of red ginseng extract (RGE) on respiratory syncytial virus (RSV) infection using in vitro cell culture and in vivo mouse models. RGE partially protected human epithelial (HEp2) cells from RSV-induced cell death and viral replication. In addition, RGE significantly inhibited the production of RSV-induced pro-inflammatory cytokine (TNF-α) in murine dendritic and macrophage-like cells. More importantly, RGE intranasal pre-treatment prevented loss of mouse body weight after RSV infection. RGE treatment improved lung viral clearance and enhanced the production of interferon (IFN-γ) in bronchoalveolar lavage cells upon RSV infection of mice. Analysis of cellular phenotypes in bronchoalveolar lavage fluids showed that RGE treatment increased the populations of CD8+ T cells and CD11c+ dendritic cells upon RSV infection of mice. Taken together, these results provide evidence that ginseng has protective effects against RSV infection through multiple mechanisms, which include improving cell survival, partial inhibition of viral replication and modulation of cytokine production and types of immune cells migrating into the lung

Adrenal ganglioneuroma with hepatic metastasis

Ganglioneuroma is the most differentiated tumor of neural crest origin and rarely arises in the adrenal gland. Ganglioneuroma is typically known to be benign, but very rarely can metastasize to distant sites. We report a case of a 31-year-old man with a huge adrenal mass with hepatic metastases

Cross Protection Against Influenza A Virus by Yeast-Expressed Heterologous Tandem Repeat M2 Extracellular Proteins

The influenza M2 ectodomain (M2e) is well conserved across human influenza A subtypes, but there are few residue changes among avian and swine origin influenza A viruses. We expressed a tandem repeat construct of heterologous M2e sequences (M2e5x) derived from human, swine, and avian origin influenza A viruses using the yeast expression system. Intramuscular immunization of mice with AS04-adjuvanted M2e5x protein vaccines was effective in inducing M2e-specific antibodies reactive to M2e peptide and native M2 proteins on the infected cells with human, swine, or avian influenza virus, mucosal and systemic memory cellular immune responses, and cross-protection against H3N2 virus. Importantly, M2e5x immune sera were found to confer protection against different subtypes of H1N1 and H5N1 influenza A viruses in naïve mice. Also, M2e5x-immune complexes of virusinfected cells stimulated macrophages to secrete cytokines via Fc receptors, indicating a possible mechanism of protection. The present study provides evidence that M2e5x proteins produced in yeast cells could be developed as a potential universal influenza vaccine

Recombinant Influenza Virus Carrying the Conserved Domain of Respiratory Syncytial Virus (RSV) G Protein Confers Protection Against RSV Without Inflammatory Disease

Respiratory syncytial virus (RSV) is one of the most important causes for viral lower respiratory tract disease in humans. There is no licensed RSV vaccine. Here, we generated recombinant influenza viruses (PR8/RSV. HA-G) carrying the chimeric constructs of hemagglutinin (HA) and central conserved-domains of the RSV G protein. PR8/RSV.HA-G virus showed lower pathogenicity without compromising immunogenicity in mice. Single intranasal inoculation of mice with PR8/RSV.HA-G induced IgG2a isotype dominant antibodies and RSV neutralizing activity. Mice with single intranasal inoculation of PR8/RSV.HA-G were protected against RSV infection as evidenced by significant reduction of lung viral loads to a detection limit upon RSV challenge. PR8/RSV.HA-G inoculation of mice did not induce pulmonary eosinophilia and inflammation upon RSV infection. These findings support a concept that recombinant influenza viruses carrying the RSV G conserved-domain can be developed as a promising RSV vaccine candidate without pulmonary disease

Immunomodulatory Activity of Red Ginseng against Influenza A Virus Infection

Ginseng herbal medicine has been known to have beneficial effects on improving human health. We investigated whether red ginseng extract (RGE) has preventive effects on influenza A virus infection in vivo and in vitro. RGE was found to improve survival of human lung epithelial cells upon influenza virus infection. Also, RGE treatment reduced the expression of pro-inflammatory genes (IL-6, IL-8) probably in part through interference with the formation of reactive oxygen species by influenza A virus infection. Long-term oral administration of mice with RGE showed multiple immunomodulatory effects such as stimulating antiviral cytokine IFN-γ production after influenza A virus infection. In addition, RGE administration in mice inhibited the infiltration of inflammatory cells into the bronchial lumens. Therefore, RGE might have the potential beneficial effects on preventing influenza A virus infections via its multiple immunomodulatory functions

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. Major changes to the guidelines include streamlining the existing quality (part A) and nonclinical (part B) sections to reflect the two decades of experience, with manufacturing and control, nonclinical evaluation, and clinical testing of plasmid DNA vaccines, as a platform technology. The urgency for gaining regulatory convergence on this topic is that development of such a platform technology as DNA vaccines for routine use immunizations will prepare manufacturers and regulators across the globe in dealing with rapid development of medical countermeasures against emerging infectious diseases even in the face of an emergency setting. Two examples are described of Zika candidate vaccines that have rapidly advanced in development based on preexisting nonclinical and clinical data that precluded the need to repeat nonclinical toxicology. This report describes the progress stemming from the most recent consultation on the guidelines, including topics discussed and consensus reached