Elwyn Griffiths

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.

Assessment of the viral safety of antivenoms fractionated from equine plasma

Abstract Antivenoms are preparations of intact or fragmented (F(ab′)2 or Fab) immunoglobulin G (IgG) used in human medicine to treat the severe envenomings resulting from the bites and stings of various animals, such as snakes, spiders, scorpions, or marine animals, or from the contact with poisonous plants. They are obtained by fractionating plasma collected from immunized horses or, less frequently, sheep. Manufacturing processes usually include pepsin digestion at acid pH, papain digestion, ammonium sulphate precipitation, caprylic acid precipitation, heat coagulation and/or chromatography. Most production processes do not have deliberately introduced viral inactivation or removal treatments, but antivenoms have never been found to transmit viruses to humans. Nevertheless, the recent examples of zoonotic diseases highlight the need to perform a careful assessment of the viral safety of antivenoms. This paper reviews the characteristics of equine viruses of antivenoms and discusses the potential of some manufacturing steps to avoid risks of viral contamination. Analysis of production parameters indicate that acid pH treatments and caprylic acid precipitations, which have been validated for the manufacture of some human IgG products, appear to provide the best potential for viral inactivation of antivenoms. As many manufacturers of antivenoms located in developing countries lack the resources to conduct formal viral validation studies, it is hoped that this review will help in the scientific understanding of the viral safety factors of antivenoms, in the controlled implementation of the manufacturing steps with expected impact on viral safety, and in the overall reinforcement of good manufacturing practices of these essential therapeutic products.

Assuring the quality, safety, and efficacy of DNA vaccines.

Scientists in academia whose research is aimed at the development of a novel vaccine or approach to vaccination may not always be fully aware of the regulatory process by which a candidate vaccine becomes a licensed product. It is useful for such scientists to be aware of these processes as the development of a novel vaccine could be problematic owing to the starting material often being developed in a research laboratory under ill-defined conditions. This paper examines the regulatory process with respect to the development of a DNA vaccine. DNA vaccines present unusual safety considerations that must be addressed during preclinical safety studies, including adverse immunopathology, genotoxicity through integration into a vaccinees chromosomes, and the potential for the formation of anti-DNA antibodies.

Confronting the next pandemic—Workshop on lessons learned from potency testing of pandemic (H1N1) 2009 influenza vaccines and considerations for future potency tests, Ottawa, Canada, July 27–29, 2010

Please cite this paper as: Hardy et al. (2011) Confronting the next pandemic—Workshop on lessons learned from potency testing of pandemic (H1N1) 2009 influenza vaccines and considerations for future potency tests, Ottawa, Canada, July 27–29, 2010. Influenza and Other Respiratory Viruses 5(6), 438–442.

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.

A global regulatory science agenda for vaccines

The Decade of Vaccines Collaboration and development of the Global Vaccine Action Plan provides a catalyst and unique opportunity for regulators worldwide to develop and propose a global regulatory science agenda for vaccines. Regulatory oversight is critical to allow access to vaccines that are safe, effective, and of assured quality. Methods used by regulators need to constantly evolve so that scientific and technological advances are applied to address challenges such as new products and technologies, and also to provide an increased understanding of benefits and risks of existing products. Regulatory science builds on high-quality basic research, and encompasses at least two broad categories. First, there is laboratory-based regulatory science. Illustrative examples include development of correlates of immunity; or correlates of safety; or of improved product characterization and potency assays. Included in such science would be tools to standardize assays used for regulatory purposes. Second, there is science to develop regulatory processes. Illustrative examples include adaptive clinical trial designs; or tools to analyze the benefit-risk decision-making process of regulators; or novel pharmacovigilance methodologies. Included in such science would be initiatives to standardize regulatory processes (e.g., definitions of terms for adverse events [AEs] following immunization). The aim of a global regulatory science agenda is to transform current national efforts, mainly by well-resourced regulatory agencies, into a coordinated action plan to support global immunization goals. This article provides examples of how regulatory science has, in the past, contributed to improved access to vaccines, and identifies gaps that could be addressed through a global regulatory science agenda. The article also identifies challenges to implementing a regulatory science agenda and proposes strategies and actions to fill these gaps. A global regulatory science agenda will enable regulators, academics, and other stakeholders to converge around transformative actions for innovation in the regulatory process to support global immunization goals.

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

Biotechnology and nanotechnology provide a growing number of innovator‐driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron–carbohydrate complexes, drug‐carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1‐day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow‐on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow‐on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow‐up were identified: (1) assessment of critical attributes to establish equivalence for follow‐on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.

WHO/Health Canada meeting on regulatory considerations for evaluation and licensing of new meningococcal Group B vaccines, Ottawa, Canada, 3-4 October 2011.

Serogroup B Neisseria meningitides (MenB) is a significant cause of endemic and epidemic outbreaks of the disease worldwide. Although polysaccharide and conjugate vaccines are available against other meningococcal serogroups, the poor immunogenicity of MenB polysaccharide has led to the development of protein-based vaccines. However, the diversity and antigenic variability of MenB strains has been a major challenge. Recently a new generation of MenB vaccines that contain conserved antigens has been developed to provide broader coverage and they are in an advanced stage of development and regulatory consideration. In October 2011, the World Health Organization and Health Canada jointly organized a consultation on regulatory considerations for the evaluation and licensing of new MenB vaccines. The aim was to seek consensus on key regulatory issues relevant to the evaluation of candidate MenB vaccines and on approaches to the standardisation of in vitro assays used in the evaluation process. Participants agreed that functional antibodies as measured in the Serum Bactericidal Activity (SBA) assay could be used to evaluate MenB vaccine efficacy and ways of improving assay standardization proposed. Approaches to bridging SBA data to large collections of strains in order to give an indication of the prospective breadth of vaccine coverage were discussed.

WHO standards for biotherapeutics, including biosimilars: an example of the evaluation of complex biological products

The most advanced regulatory processes for complex biological products have been put in place in many countries to provide appropriate regulatory oversight of biotherapeutic products in general, and similar biotherapeutics in particular. This process is still ongoing and requires regular updates to national regulatory requirements in line with scientific developments and up‐to‐date standards. For this purpose, strong knowledge of and expertise in evaluating biotherapeutics in general and similar biotherapeutic products, also called biosimilars, in particular is essential. Here, we discuss the World Health Organizations international standard‐setting role in the regulatory evaluation of recombinant DNA–derived biotherapeutic products, including biosimilars, and provide examples that may serve as models for moving forward with nonbiological complex medicinal products. A number of scientific challenges and regulatory considerations imposed by the advent of biosimilars are described, together with the lessons learned, to stimulate future discussions on this topic. In addition, the experiences of facilitating the implementation of guiding principles for evaluation of similar biotherapeutic products into regulatory and manufacturers’ practices in various countries over the past 10 years are briefly explained, with the aim of promoting further developments and regulatory convergence of complex biological and nonbiological products.

The WHO network of collaborating centres on standardization and regulatory evaluation of vaccines.

WHO Collaborating Centres (CCs) form part of an international collaborative network set up by WHO in support of its mandated programme at the country, intercountry, regional, interregional and global levels, as appropriate. As part of its mandate in the area of biologicals, WHO has broadened the scope of its work and has expanded the range of activities devoted to the establishment of international standards for vaccines. In line with global immunization goals, the need for standards for evaluation of quality, safety and efficacy of new vaccines, as well as those that have been in use for a long time, has significantly increased. Furthermore, complex issues related to new production methodologies, more sophisticated techniques for characterization and laboratory testing, and for nonclinical and clinical evaluation of vaccines have raised a number of regulatory challenges for WHO when requested to assist its Member States. In this context, CCs in the area of standardization of vaccines and biotherapeutics (excluding blood products) have provided technical assistance and have broadened the scope of their work over time. In the area of standardization and regulatory evaluation of vaccines, WHO currently has six CCs as well as one candidate centre for which the designation process has been initiated and a further three candidate centres with great potential. The purpose of the meeting held on 24-26 April 2012 was to improve understanding of WHOs priorities in setting standards, to facilitate their implementation, and to increase transparency of the roles and responsibilities of CCs. The meeting was also an excellent opportunity to explore possibilities for improving collaboration between WHO and CCs, as well as among CCs themselves by working as a CC network. All CCs expressed a wish for increased interaction, information-sharing, collaboration and other ways of working together that may lead to cross-fertilization between the CCs. Synergy was recognized as a significant mechanism for leveraging existing resources in responding to global public health challenges and in addressing WHOs priorities. Agreement was reached for operating as a network of CCs.