Animal models for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19), an emerging respiratory infection caused by the introduction of a novel coronavirus into humans late in 2019 (first detected in Hubei province, China). As of 18 September 2020, SARS-CoV-2 has spread to 215 countries, has infected more than 30 million people and has caused more than 950,000 deaths. As humans do not have pre-existing immunity to SARS-CoV-2, there is an urgent need to develop therapeutic agents and vaccines to mitigate the current pandemic and to prevent the re-emergence of COVID-19. In February 2020, the World Health Organization (WHO) assembled an international panel to develop animal models for COVID-19 to accelerate the testing of vaccines and therapeutic agents. Here we summarize the findings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19.

Report of the third conference on next-generation sequencing for adventitious virus detection in biologics for humans and animals.

Next-generation sequencing (NGS) has been proven to address some of the limitations of the current testing methods for adventitious virus detection in biologics. The International Alliance for Biological Standardization (IABS), the U.S. Food and Drug Administration (FDA), and the European Directorate for the Quality of Medicines and Healthcare (EDQM) co-organized the "3rd Conference on Next-generation Sequencing for Adventitious Virus Detection in Biologics for Humans and Animals", which was held on September 27-28, 2022, in Rockville, Maryland, U.S.A. The meeting gathered international representatives from regulatory and public health authorities and other government agencies, industry, contract research organizations, and academia to present the current status of NGS applications and the progress on NGS standardization and validation for detection of viral adventitious agents in biologics, including human and animal vaccines, gene therapies, and biotherapeutics. Current regulatory expectations were discussed for developing a scientific consensus regarding using NGS for detection of adventitious viruses. Although there are ongoing improvements in the NGS workflow, the development of reference materials for facilitating method qualification and validation support the current use of NGS for adventitious virus detection.

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. The meeting participants applauded the leading role taken by the WHO in providing a much-needed streamlined approach for development and evaluation of SBPs which will provide efficient and cost-effective product development and increase patient access to treatments. It was recognized that the principles as currently described in the draft WHO guidelines are based on sound science and experience gained over the last fifteen years of biosimilar approvals. However, since these guidelines when finalised will constitute the global standard for biosimilar evaluation and assist national regulatory authorities in establishing revised guidance and regulatory practice in this complex area, it was felt that further revision and clarity on certain perspectives in specific areas was necessary to dispel uncertainties arising in the current revised version. This report describes the principles in the draft guidelines, including topics discussed and consensus reached.

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. This article describes the progress made and the regulatory landscape changes for biosimilars in 21 countries during the past ten years. Based on the information from regulators and from publicly available data, the following has been identified: 1) WHO guidelines have contributed to setting the regulatory framework for biosimilars in countries and increasing regulatory convergence at global level; 2) terminology used for biosimilars is more consistent than in the past; 3) biosimilars are now approved in all participating countries; and 4) the dominant product class for candidate biosimilars under development is monoclonal antibodies.

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. Over the past years, the requirements in WHO Recommendations/Guidelines for conducting the test evolved such that it could be waived for routine release of product once consistency of production was established to the satisfaction of the NRA, or that the need for this test should be discussed and agreed with the NRA. However, some users of WHO written standards for biologicals (i.e., Recommendations, Guidelines) and WHO specifications for pharmaceuticals (i.e., The International Pharmacopoeia) requested that the innocuity test be deleted from WHO written standards based on its lack of specificity and scientific relevance. In response to that request, we studied the history of this test and its use by the member states of WHO, and the recommendations in WHO written standards. The outcomes of the study were reviewed by the relevant WHO Expert Committee on Biological Standardization and Expert Committee on Specifications for Pharmaceutical Products who then decided to discontinue this test in WHO Recommendations for vaccines and biologicals and to omit the test from The International Pharmacopoeia.

Report of the second international conference on next generation sequencing for adventitious virus detection in biologics for humans and animals.

The IABS-EU, in association with PROVAXS and Ghent University, hosted the "2nd Conference on Next Generation Sequencing (NGS) for Adventitious Virus Detection in Human and Veterinary Biologics" held on November 13th and 14th 2019, in Ghent, Belgium. The meeting brought together international experts from regulatory agencies, the biotherapeutics and biologics industries, contract research organizations, and academia, with the goal to develop a scientific consensus on the readiness of NGS for detecting adventitious viruses, and on the use of this technology to supplement or replace/substitute the currently used assays. Participants discussed the progress on the standardization and validation of the technical and bioinformatics steps in NGS for characterization and safety evaluation of biologics, including human and animal vaccines. It was concluded that NGS can be used for the detection of a broad range of viruses, including novel viruses, and therefore can complement, supplement or even replace some of the conventional adventitious virus detection assays. Furthermore, the development of reference viral standards, complete and correctly annotated viral databases, and protocols for the validation and follow-up investigations of NGS signals is necessary to enable broader use of NGS. An international collaborative effort, involving regulatory authorities, industry, academia, and other stakeholders is ongoing toward this goal.

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. Erythropoietin has been identified as one of the important glycosylated therapeutic proteins and a good example to illustrate how structural characteristics would affect product efficacy and safety. The case study illustrates biosimilarity assessment of a candidate of erythropoietin biosimilar and the important quality attributes that need to be considered in order to understand the importance of structure-function relationships as they contribute to the stepwise evaluation of biosimilarity. This paper reflects the outcomes of the case study exercise and discussion from two WHO implementation workshops held in Ghana (September 2015) and Denmark (July 2017).

Prevalence of oncogenic Human papillomavirus and genetic diversity in the L1 gene of HPV16 HPV 18 HPV31 and HPV33 found in women from Vojvodina Province Serbia.

The main purpose of this paper is to estimate the pre-vaccination prevalence of 12 hrHPV types among 564 women from Vojvodina province (Serbia). The corrected contingency coefficient (Ccorr) was used to estimate the importance of association of examined HPV types and cytological diagnosis. The highest association with the abnormal cytology was observed for HPV 16 (Ccorr = 0.493) in all age groups of participants. The effect of HPV 16 was especially clear within the group of women older than 35 years (Ccorr = 0.691), compared with women younger than 35 (Ccorr = 0.333). The molecular characterization at the level of L1 gene of HPV 16, 18, 31 and 33 variants was for the first time assessed in our region. Nearly all HPV 16 isolates cluster with variant lineage A (96.4%) the remaining isolates clustering with variant lineage D. All of HPV 18 and HPV 33 isolates are clustering within the lineage A while isolates of HPV 31 group with lineages A and C. This contributes to understanding of intrinsic geographical and biological differences of examined HPV types and could be useful for development of cervical cancer screening strategies in Vojvodina (Serbia) and diagnosis of HPV related cervical cancer in general.

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. 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.

En 2014, l'Assemblée mondiale de la Santé a adopté une résolution qui reconnaissait l'importance d'améliorer l'accès aux produits biothérapeutiques, de les rendre moins coûteux et de garantir leur qualité, innocuité et efficacité. Les biosimilaires sont des produits biothérapeutiques similaires à des produits de référence déjà autorisés, qui sont généralement développés après expiration des brevets protégeant les produits originaux. Leur introduction sur le marché a le potentiel de réduire considérablement les coûts des médicaments, améliorant ainsi la disponibilité des traitements pour les patients. Mais certaines barrières font encore obstacle à l'entrée sur le marché des biosimilaires. Cet article évoque les facteurs qui créent ces barrières et explique l'importance d'une supervision réglementaire sur tout le cycle de vie des produits biosimilaires. Cet article décrit également le rôle que les organismes de réglementation pourraient jouer pour améliorer la confiance à l'égard des biosimilaires, notamment: (i) en établissant une supervision réglementaire des biosimilaires sur tout leur cycle de vie, depuis leur développement jusqu'à la surveillance postérieure à leur autorisation de mise sur le marché et en s'assurant que seuls des biosimilaires de grande qualité, sûrs et efficaces sont commercialisés; (ii) en veillant à ce que les autorités de réglementation aient la capacité suffisante pour évaluer et contrôler la qualité, l'innocuité et l'efficacité des biosimilaires pendant tout leur cycle de vie; et (iii) en surveillant l'utilisation des biosimilaires dans les systèmes publics de santé, en collaboration avec d'autres parties prenantes.

La Asamblea de la Organización Mundial de la Salud en 2014 adoptó una resolución que reconoce la importancia de aumentar el acceso a productos bioterapéuticos, de mejorar su asequibilidad y asegurar su calidad, seguridad y eficacia. Los medicamentos biosimilares son productos bioterapéuticos similares a productos de referencia con licencia y usualmente se desarrollan después de que las patentes de los productos originales ya hayan expirado. Su introducción al mercado puede reducir sustancialmente los costes de los medicamentos, por lo tanto, mejora la disponibilidad del tratamiento para los pacientes. Sin embargo, existen barreras de acceso al mercado para los biosimilares. Este articulo trata los factores que dan lugar a esas barreras y explica la importancia de una supervisión reguladora durante el ciclo de vida de los biosimilares. El documento también describe el papel que pueden tener los reguladores para aumentar la confianza en los biosimilares de la siguiente forma: (I) estableciendo supervisiones reguladoras de biosimilares durante su ciclo de vida, desde el desarrollo hasta la supervisión post licencia, y asegurando que solamente biosimilares de alta calidad, seguros y eficaces estén disponibles en el mercado; (ii) asegurando que las autoridades reguladoras tengan la capacidad adecuada para evaluar y controlando la calidad, la seguridad y la eficacia de los biosimilares durante su ciclo de vida; y (iii) controlando el uso de biosimilares en los sistemas de salud públicos en colaboración con otras partes interesadas.

Report of the international conference on next generation sequencing for adventitious virus detection in biologicals.

A fundamental aspect of biological product safety is to assure absence of adventitious agents in the final product. Next-generation or high-throughput sequencing (NGS/HTS) has recently demonstrated detection of viruses that were previously missed using the recommended routine assays for adventitious agent testing of biological products. This meeting was co-organized by the International Alliance for Biological Standardization (IABS) and the U.S. Food and Drug Administration (FDA) to assess the current status and discuss the readiness of NGS for adventitious virus detection in biologics. The presentations included efforts for standardization, case studies on applications in biologics, comparison with routine virus detection assays, and current regulatory thinking. Participants identified the need for standard reference reagents, well-annotated databases, large data storage and transfer capacity, personnel with relevant expertise, particularly in bioinformatics; and harmonization of international regulations for testing biologic products and reagents used for their manufacturing. We hope this meeting summary will be of value to regulators and industry for considerations of NGS applications for adventitious virus detection in biologics.

Report of the international conference on manufacturing and testing of pluripotent stem cells.

Sessions included an overview of past cell therapy (CT) conferences sponsored by the International Alliance for Biological Standardization (IABS). The sessions highlighted challenges in the field of human pluripotent stem cells (hPSCs) and also addressed specific points on manufacturing, bioanalytics and comparability, tumorigenicity testing, storage, and shipping. Panel discussions complemented the presentations. The conference concluded that a range of new standardization groups is emerging that could help the field, but ways must be found to ensure that these efforts are coordinated. In addition, there are opportunities for regulatory convergence starting with a gap analysis of existing guidelines to determine what might be missing and what issues might be creating divergence. More specific global regulatory guidance, preferably from WHO, would be welcome. IABS and the California Institute for Regenerative Medicine (CIRM) will explore with stakeholders the development of a practical and innovative road map to support early CT product (CTP) developers.

The Role of Genetic Polymorphisms in Chronic Pain Patients.

It is estimated that the total annual financial cost for pain management in the U.S. exceeds 100 billion dollars. However, when indirect costs are included, such as functional disability and reduction in working hours, the cost can reach more than 300 billion dollars. In chronic pain patients, the role of pharmacogenetics is determined by genetic effects on various pain types, as well as the genetic effect on drug safety and efficacy. In this review article, we discuss genetic polymorphisms present in different types of chronic pain, such as fibromyalgia, low back pain, migraine, painful peripheral diabetic neuropathy and trigeminal neuralgia. Furthermore, we discuss the role of CYP450 enzymes involved in metabolism of drugs, which have been used for treatment of chronic pain (amitriptyline, duloxetine, opioids, etc.). We also discuss how pharmacogenetics can be applied towards improving drug efficacy, shortening the time required to achieve therapeutic outcomes, reducing risks of side effects, and reducing medical costs and reliance upon polypharmacy.

Scientific considerations for the regulatory evaluation of cell therapy products.

Cell therapy involves the administration of a viable somatic cell preparation to a patient for the treatment of a disease or traumatic damage. Because cell therapies are complex and very different from traditional biological products, they present significant challenges for regulatory authorities, manufacturers, developers, health care providers, and patients involved in their application. Like other emerging areas of biomedical research and development, there are many issues where regulatory views and decisions among countries and regions may differ due to minimal scientific evidence to support safety and efficacy, and lack of experience with these novel treatments. A brief overview of the current regulatory landscape for cell-based therapies is presented, and the need for a global effort to develop a set of common principles that may serve to facilitate the regulatory evaluation and market availability of these products is identified. In addition, a number of elements that could form a core consensus package of requirements for evaluating human cell therapy products is presented in the supplemental material which should be read in conjunction with the manuscript.

Scientific and regulatory challenges in evaluating clinical trial protocols for HIV-1/AIDS vaccines - A review from a regulatory perspective.

Clinical development of prophylactic HIV/AIDS vaccines presents many scientific challenges that result in challenges for regulators reviewing clinical trial applications (CTAs). The World Health Organization (WHO) has the responsibility to provide technical support to these regulators. The search for an HIV/AIDS vaccine will only succeed through well-designed, -conducted and -controlled human efficacy studies reviewed and approved by regulators in countries worldwide, particularly in countries where the epidemic has hit hardest, such as in sub-Saharan Africa and Asia. This review summarizes the current candidates in development and focuses on challenges regulators face when reviewing CTAs, such as the evolving landscape of "standard of prevention," trials in adolescents, adaptive trial designs, correlates of protection and their analysis, and access to successful vaccines. There are many unknowns in the field of HIV/AIDS vaccine development and often, there is not a clear right or wrong approach because of the scientific challenges described in this review. Consequently, regulators should not feel that decisions need be made in isolation, when there are many available international collaborative efforts and opportunities to seek expert advice. The WHO provides many such opportunities and support to regulators across the globe.

Review of efficacy trials of HIV-1/AIDS vaccines and regulatory lessons learned: A review from a regulatory perspective.

The clinical development of prophylactic HIV-1/AIDS vaccines is confounded by numerous scientific challenges and these in turn result in challenges to regulators reviewing clinical trial applications (CTAs). The search for an HIV-1/AIDS vaccine will only succeed through the conduct of well-designed, well-conducted and well-controlled human efficacy studies. This review summarizes relevant context in which HIV vaccines are being investigated and the six completed efficacy trials of various candidate vaccines and regimens, as well as the lessons learned from them relevant to regulatory evaluation. A companion review focuses on the scientific challenges regulators face and summarizes some current candidates in development. The lessons learned from the completed efficacy trials will enable the development of better designed, potentially more efficient efficacy trials in future. This summary, supported by the World Health Organization (WHO), is unique in that it is meant to aid regulators in understanding the valuable lessons gained from experience in the field to date.

High-risk human papilloma virus genotypes in cervical carcinoma of Serbian women: Distribution and association with pathohistological findings.

A significant role of high-risk Human papilloma viruses (HR HPV) in the development of cervical carcinoma is well known. HR HPV 16 and 18 account for approximately 70% of all cases of cervical cancer worldwide. The incidence of cervical cancer in Serbia, is one of the highest in Europe. The aim of our study was to investigate the distribution of HR HPV types in cervical carcinoma of Serbian women, as well as association between the HPV types and pathohistological findings. The study included 80 archival cervical cancer tissues from the same number of patients. The presence of HPV DNA was determined using MY09/MY11 primers for L1 gene and GP1/GP2 primers for E1 gene. HPV was detected in 78.75% tissues. HR HPV genotypes found in the decreasing order of frequency were: HPV16 (80.39%), HPV33 (7.84%), HPV58 (5.88%), HPV18 (1.96%), HPV45 (1.96%) and HPV53 (1.96%). The examined tissues were 91.25% squamous cell carcinomas and 8.75% adenocarcinoma. The high frequency of HPV 16 was observed in both types of carcinoma (80.8% and 75%, respectively) while the prevalence of HPV18 was low. These results may contribute to the implementation of cervical carcinoma prevention program in Serbia, including the selection of the most appropriate vaccine and immunization program.

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. The following topics were discussed by the working groups: clinical criteria for biosimilarity, extrapolation approach and the overall regulatory decision making process. In order to determine typical pitfalls in the design of a SBP clinical programme and evaluate the gap of knowledge, amongst different industry and regulatory stakeholders on the appraisal of the data arising from SBP clinical studies, we have presented two fictional but realistic clinical case studies. The first case consists of the fictional development programme for an infliximab SBP candidate. The second case describes clinical studies proposed for a fictional rituximab SBP candidate. In the first scenario a highly similar quality profile has been taken forward into clinical studies whereas there was an important residual difference in functional attributes for the rituximab SBP candidate. These case studies were presented at the WHO implementation workshop for the WHO guidelines on evaluation of similar biotherapeutic products held in Seoul, Republic of Korea, in May 2014. The goal was to illustrate the interpretation of the clinical data arising from studies with SBP candidates and elicit knowledge gaps in clinical assessment. This paper reflects the outcome of the exercise and discussions held in Seoul and offers an analysis of the case studies as a learning opportunity on clinical development and evaluation of SBPs.

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. 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.