Ivana Knezevic

Challenges in the evaluation and licensing of new pneumococcal vaccines, 7-8 July 2008, Ottawa, Canada

The introduction of seven valent pneumococcal conjugate vaccine (7vPnC) into immunization programmes has led to a significant reduction in invasive disease due to Streptococcus pneumoniae. New conjugate pneumococcal vaccine formulations containing additional serotypes are at advanced stages of clinical development and are expected to be available in the near future. There are also a number of on-going initiatives to facilitate the introduction of pneumococcal conjugate vaccines into the immunization programmes of developing countries. These initiatives are dependent upon the vaccines being satisfactorily licensed and subsequently pre-qualified by the WHO for use by UN agencies. Recommendations for the production and control of pneumococcal conjugate vaccines were established by WHO in 2003 and have served as a basis for national requirements for the evaluation and licensing of these products. Much progress has been made since that time and a consultation held in Ottawa, Canada, in July 2008 aimed to provide regulators and manufacturers with further guidance on the criteria for evaluating and licensing of new pneumococcal conjugate vaccines taking account of recent developments. The principal conclusion of the meeting was that the current WHO recommendations, in which the demonstration of immunological non-inferiority to the licensed 7vPnC vaccine is proposed as the main basis for approval, continue to provide a solid basis for the evaluation of pneumococcal conjugate vaccines and may be referred to when assessing new vaccines for licensure and pre-qualification. Uncertainties regarding serological criteria for assessing the efficacy of new conjugate vaccines against invasive pneumococcal disease were discussed in detail and proposals made for handling complex data. In particular, it was emphasized that all relevant immunological data should be taken into account when comparing new pneumococcal conjugate vaccines with licensed 7vPnC vaccine. These include the measurement of the total amount of anticapsular IgG as well as the demonstration of functionality of vaccine-induced antibodies, by verifying their ability to opsonize and promote the killing of pneumococcal serotypes, and the demonstration of immunological priming. It was agreed that new information on assay performance and on the effectiveness of currently licensed 7vPnC vaccine, as assessed in routine mass immunization programmes, should both be included in any update of the WHO recommendations. A detailed meeting report is available at the WHO web site for biologicals: http://www.who.int/biologicals/publications/meetings/areas/vaccines/pneumococcal/en/index.html.

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.

WHO Working Group on Technical Specifications for Manufacture and Evaluation of Yellow Fever Vaccines, Geneva, Switzerland, 13-14 May 2009

In May 2009, a group of international experts on dengue, vaccine quality and clinical evaluation met together (i) to review disease, vaccine pipeline, quality issues in manufacturing, issues of environmental risk assessment, nonclinical and clinical evaluation of live recombinant dengue vaccines and (ii) to initiate revising WHO guidelines for the production and quality control of candidate tetravalent dengue vaccines (live). This report summarizes an exchange of views on scientific and technical issues related to the quality, safety and efficacy of candidate dengue vaccines. Recognizing live dengue vaccines are the major vaccines in the clinical pipeline, the Working Group agreed (i) to focus on live dengue vaccines in the revision of the WHO guidelines and (ii) to add new guidelines on nonclinical and clinical evaluation, and environmental risk assessment for live dengue vaccines in the revision.

Adventitious agents in viral vaccines: Lessons learned from 4 case studies

Since the earliest days of biological product manufacture, there have been a number of instances where laboratory studies provided evidence for the presence of adventitious agents in a marketed product. Lessons learned from such events can be used to strengthen regulatory preparedness for the future. We have therefore selected four instances where an adventitious agent, or a signal suggesting the presence of an agent, was found in a viral vaccine, and have developed a case study for each. The four cases are: a) SV40 in polio vaccines; b) bacteriophage in measles and polio vaccines; c) reverse transcriptase in measles and mumps vaccines; and d) porcine circovirus and porcine circovirus DNA sequences in rotavirus vaccines. The lessons learned from each event are discussed. Based in part on those experiences, certain scientific principles have been identified by WHO that should be considered in regulatory risk evaluation if an adventitious agent is found in a marketed vaccine in the future.

WHO Informal Consultation on standardization and evaluation of BCG vaccines Geneva, Switzerland 22-23 September 2009.

The current World Health Organization Requirements for BCG vaccine are in need of revision to address the diversity of sub-strains used for production, potential improvements of quality control assays for lot release, and the establishment of sub-strain specific Reference Reagents. A consultation meeting was organized to discuss issues regarding the standardization and evaluation of BCG vaccines in the forum of regulators, BCG vaccine manufacturers, developers of selected new live tuberculosis (TB) vaccines and researchers. The development of new recombinant BCG and live attenuated TB vaccines and the characterisation of different BCG sub-strains using state-of-the-art technologies were also reviewed. The objective of the meeting was to revise and update the current recommendations focused on the scope, terminology, manufacturing issues, and the incorporation of new reference reagents and new quality control tests.

WHO Study Group on cell substrates for production of biologicals, Geneva, Switzerland, 11-12 June 2007.

For many years, the World Health Organization (WHO) has provided global leadership in defining technical specifications for quality assurance and safety of biological medicines produced in cell substrates. Current WHO requirements for the use of animal cells as substrates for production of vaccines and other biologicals were adopted by the WHO Expert Committee on Biological Standardization in 1996 (WHO TRS 878). Since then, significant progress especially in the development of vaccines in novel continuous cell lines of mammalian origin as well as in insect cells has been made and consequently there is an increasing need for the re-evaluation of existing criteria for the acceptability of such cell lines. In addition there is also a need to consider new issues in cell substrate safety arising from these new cell types and developments in technology and scientific knowledge. In response to these demands, the WHO Study Group on Cell Substrates was formed in 2006 to initiate revision of WHO requirements and to address the need for further research in this area. At its second meeting on 11-12 June 2007, the Study Group reviewed scientific data that would form the basis for new recommendations and made a number of proposals for further investigations. The Study Group is working on the preparation of a revised WHO document, and a broad consultation with regulators, manufacturers, and other relevant parties is planned for 2008.

Report of an international collaborative study to establish the suitability of using modified ATP assay for viable count of BCG vaccine.

As part of the World Health Organisation (WHO) initiative to update the current requirements for BCG vaccine a collaborative study was carried out to establish the robustness, reproducibility and the suitability of the modified ATP assay. This assay was developed by Statens Serum Institut, Denmark, as a potential replacement of the method for detection of viable counts of BCG vaccine which is routinely used as a quality control test for lot release. Two BCG preparations, of same strain but different production methods, were tested. For each preparation, two different storage conditions of -20 or 37 degrees C were used in order to establish the suitability of this assay for testing heat-treated BCG vaccine as in the temperature stability test. The lyophilised BCG samples were tested using the ATP reagents from the same source and same principle of testing but some procedural modifications were allowed to accommodate different equipment and resource availability in different laboratories. Data from four laboratories showed that the heat-treated BCG samples contained significantly lower ATP content per sample than the untreated control stored at -20 degrees C. Three laboratories gave consistent mean ATP contents, especially for control samples, even with variations in testing protocol. The present study showed that this modified ATP assay is very robust and can be reproducible. Once the correlation of cultural viable count and ATP content of a BCG vaccine product has been established, this rapid alternative assay may be used to monitor BCG viable count. Due to the fact that this study was small, further investigation is planned. A collaborative study will be carried out using this modified ATP assay in parallel with the cultural viable count method in the establishment of the replacement of the WHO International Reference Preparation of BCG vaccine.

Stability evaluation of vaccines: WHO approach.

The stability of vaccines has a major impact on the success of immunization programmes worldwide. In line with this, clear definition of the stability characteristics of a vaccine is of critical importance. One of the concerns at country level is whether vaccines will remain potent on its way from the manufacturer, through the distribution channels, to the final users and vaccine recipients. In response to the requests for assistance in defining stability profile of vaccines, the Expert Committee on Biological Standardization (ECBS) in October 2006 agreed that new WHO guidelines be established on stability evaluation of vaccines (http://www.who.int/biologicals/publications/trs/areas/vaccines/stability/en/index.html). This document applies to all vaccines against infectious diseases. The aim of this guideline is to provide the scientific basis and guiding principles for evaluation of vaccine stability for the purpose of clinical trial approval, licensing, and post-licensure monitoring. As part of its initiative to promote use of vaccines of assured quality, WHO emphasizes the role of National Regulatory Authorities (NRAs) and National Control Laboratories (NCLs) in overall vaccine evaluation, including stability assessment. While recognizing that manufacturers are responsible for the quality of the vaccines they produce, compliance with vaccine quality specifications is part of regulatory oversight. This article provides basic information about WHO international standards as well as key definitions and principles for stability evaluation of vaccines that are elaborated in detail in the above mentioned guidance document.

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 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. The immune response is influenced by many factors and data generated in the pre-licensure studies are usually somewhat difficult for regulatory review. The knowledge and expertise required for this requires a thorough understanding of animal and human immunology as well as specific product characteristics, including mechanism of action, antibody assays and assessment of results in a given clinical context. The appropriate interpretation of immunogenicity data is of critical importance for defining the safety profile of a monoclonal antibody. Two case studies described in this paper were prepared to mimic a real situation in which regulators need to evaluate immunogenicity studies conducted by manufacturers of monoclonal antibody products. The specific objective of the case studies was to illustrate assessment of unwanted immunogenicity and the important factors that need to be considered in this context. Regulators and manufacturers who attended the World Health Organization (WHO) implementation workshop on Evaluation of Biotherapeutic Products, held in Seoul, Republic of Korea, in May 2014, participated in the case studies and provided valuable input. This article outlines the main aspects of immunogenicity discussed in these case studies and a summary of the lessons learned at this occasion.