Collaborative study for the validation of serological methods for potency testing of diphtheria toxoid vaccine (part 2).

The study is a contribution to the EDQM's efforts to meet some of the expectations of the 3 Rs: Replacement, Reduction and Refinement of animal assays as proposed by Russell and Burch in 1959 and adopted by the European Union in 1986, and specifically to validate alternative assays to replace, for batch-release purposes, the European Pharmacopoeia (Ph. Eur.) in vivo direct challenge procedures for the potency determination of diphtheria toxoid vaccines. The study results may be used in support of the replacement of the multi-dilution direct challenge procedures in different animal models by a single dilution serology test, where appropriate, and to use sera from the same animals for potency testing of several components in combined vaccines. With regard to the latter, the present study explores the possibility of testing both diphtheria and tetanus toxoid potencies using serum from the same animals.

[Alternative immunization schedule and combined vaccines in paediatric practice]. / Alternatywny program szczepien i szczepionki skojarzone w praktyce pediatrycznej.

European countries individually implement their national immunisation schedules adjusted to their economic situation, epidemiological risks and other socio-political factors. The polish schedule of compulsory vaccination includes an obligatory part financed by the state and the recommended one financed individually by parents of patients themselves. The officially registered multi component vaccines my become an alternative for the obligatory schedules. Benefits of combined vaccine comprise: reduced number injections per visit and reduced number of exposures to possible injection pain; less or no exposure to thiomersal; less time spent in doctor visit, less waste and increased injection safety with fewer syringes, reduced immunisation programme costs and facilitated addition data collection through easier documentation and simplified implementation of immunisation programmes.

Prelicensure evaluation of combination vaccines.

There is considerable public health interest in licensing safe and effective combination vaccines. Because combination vaccines may progress rapidly from phase 1 to a pivotal phase 2 immunogenicity trial, a rigorous approach to address product issues early in development is warranted. Clinical studies to evaluate the safety, immunogenicity, and (when necessary) clinical end point efficacy of combination vaccines should be randomized and well controlled in most cases. A large phase 3 safety study (i.e., a study that enrolls thousands of vaccinees) should be included in the development plan if a phase 3 (clinical end point) efficacy trial will not be conducted. Often, the new combination vaccine under development contains immunogens that have all been previously licensed, have demonstrated efficacy in earlier clinical trials, or both. For such products, comparative immunogenicity data may be sufficient to support efficacy. When applicable, clinical data to support simultaneous administration with other relevant vaccines should be obtained. Given the complexity of combination vaccine development, early consultation with United States Food and Drug Administration can be invaluable.

Perspectives on the manufacture of combination vaccines.

Evolving regulatory requirements in the United States and Europe create major challenges for manufacturers tasked with production of vaccines that contain > or =9 separate antigens capable of protecting against infectious diseases, such as diphtheria, tetanus, pertussis, polio, hepatitis B, and Haemophilus influenza b, in a single shot. This article describes 10 steps that can facilitate the process of licensing these complex vaccines. It also points out problems associated with the use of animal tests for the crucial step of potency testing for batch release caused by the inherent variability of such tests and the difficulties of interpreting their results.

Manufacturing issues with combining different antigens: a regulatory perspective.

The regulation of biological products is conducted within the framework Title 21 of the US Code of Federal Regulations (CFR). These regulations describe product and clinical testing requirements for drugs and biological products, as well as the requirements for licensure of such products. The requirements outlined in the CFR also apply to combination vaccines. In addition, the Center for Biologics Evaluation and Research has issued a Guidance to Industry document that discusses the manufacturing, testing, and clinical evaluation of combination vaccines. However, as the complexity of mixing the different antigens increases, the challenges associated with product development (e.g., demonstration of comparability of the components and lot consistency) require early interactions with the US Food and Drug Administration. The many areas of difficulty in the arena of combination vaccine development underscore the need for continued reevaluation of current guidance documents in addressing the increasing complexity of vaccines.

Vaccine industry perspective of current issues of good manufacturing practices regarding product inspections and stability testing.

I address 2 important topics of current good manufacturing practices as they apply to vaccine products: product inspections and stability testing. The perspective presented is that of regulated industry. There are 2 major categories of product/facility inspections: those occurring before licensure of a vaccine product and those occurring after a vaccine product is licensed. The logistics and focus of each inspection type, the preapproval inspection, and the required biennial inspection are discussed, as are guidance and recommendations for achieving successful inspections. The requirements, guidance, and recommendations regarding the type, amount, and extensiveness of stability data for vaccine products are presented. The discussion details the potential differences in the amount and type of data required for products that are not yet licensed versus marketed products. Guidance, from a regulated industry perspective, regarding the design and implementation of a successful stability program is also discussed.

Potency tests of combination vaccines.

Combination vaccines differ from single-component vaccines in composition and in how they are manufactured, which poses significant challenges to implementing effective quality-control tests, including measurement of potency. Because each combination vaccine is unique, existing guidelines often fail to provide sufficient information to overcome the inevitable problems encountered when developing and implementing potency tests. Success depends on careful consideration of scientific and regulatory issues. Significant problems may occur if potential interactions between different components in the vaccine are not taken into account during product and test development. Thorough analysis of critical assay parameters and attention to scientific and statistical justifications for the test increase the likelihood of its acceptance. Practical approaches based on experience include rational design of validation studies, complete evaluation and documentation of the potency tests under the conditions in which they are to be applied, and establishing the relationship between production lots of vaccine and lots used in clinical trials.

Perspectives on the state of combination vaccines: summary of the rapporteur for the International Symposium on Combination Vaccines.

Recent advances in immunology, biotechnology, and other sciences now give the prospect of a wide variety of new vaccines that can bring further improvements in health but that pose some theoretical issues relating to safety and efficacy, as well as practical issues relating to logistics, number of injections, and other factors. Combination vaccines are essential if society is to take full advantage of new vaccines that can further reduce the burden of infectious diseases in this country and around the world. The major issues relating to combination vaccines are much the same today as those discussed at a 1993 meeting. However, considerable progress has been made in developing solutions to the problems, and prospects are good that many of these issues will be resolved in the next 2-3 years.

Current status and future trends in vaccine regulation--USA.

In regulating vaccines, the US Food and Drug Administration (FDA) is governed by the Code of Federal Regulations. These regulations serve as the framework for product characterization, as well as preclinical and clinical testing strategies. Novel vaccine approaches such as combination vaccines, vectored vaccines, new adjuvants, and novel delivery systems pose unique regulatory challenges for the FDA. If US licensure is sought, communication with the FDA throughout the clinical development of a product is essential to identify and implement the appropriate strategies for demonstrating the safety and effectiveness of a new product.

Review of current preclinical testing strategies for bacterial vaccines.

A wide variety of bacterial vaccines is in various stages of preclinical and clinical development. These products range from whole killed or live attenuated bacterial organisms to purified proteins, peptides and plasmid DNA. Although preclinical strategies may be directed by a set of common guidelines focused on demonstrating safety and biological activity, the exact developmental scheme will depend on product-specific characteristics. In general, preclinical data should support the proposed clinical formulation and include detailed information on the source and quality of starting materials, manufacturing processes, characterization of bacterial seed stocks, potency, general safety, purity, and identity. Data describing product validation and testing may be appropriate depending on the type of product, e.g., genetic stability for recombinant constructs, details on inactivation or attenuation methods for organisms or toxins, demonstration of potency of combination products, and safety and toxicology studies of plasmid DNA vaccines or vaccines with novel adjuvants. The choice of dose, route, and formulation to be used clinically may be greatly affected by rigorous preclinical developmental strategies.