Impact of BRICS' investment in vaccine development on the global vaccine market.

Brazil, the Russian Federation, India, China and South Africa--the countries known as BRICS--have made considerable progress in vaccine production, regulation and development over the past 20 years. In 1993, all five countries were producing vaccines but the processes used were outdated and non-standardized, there was little relevant research and there was negligible international recognition of the products. By 2014, all five countries had strong initiatives for the development of vaccine technology and had greatly improved their national regulatory capacity. South Africa was then the only BRICS country that was not completely producing vaccines. South Africa is now in the process of re-establishing its own vaccine production and passing beyond the stage of simply importing, formulating and filling vaccine bulks. Changes in the public sector's price per dose of selected vaccines, the global market share represented by products from specific manufacturers, and the attractiveness, for multinational companies, of partnership and investment opportunities in BRICS companies have all been analysed. The results indicate that the BRICS countries have had a major impact on vaccine price and availability, with much of that impact attributable to the output of Indian vaccine manufacturers. China is expected to have a greater impact soon, given the anticipated development of Chinese vaccine manufacturers in the near future. BRICS' accomplishments in the field of vaccine development are expected to reshape the global vaccine market and accelerate access to vaccines in the developing world. The challenge is to turn these expectations into strategic actions and practical outcomes.

Le Brésil, la Fédération de Russie, l'Inde, la Chine et l'Afrique du Sud ­ les pays connus sous le nom de BRICS ­ ont fait des progrès considérables dans la production, la régulation et le développement des vaccins au cours des 20 dernières années. En 1993, les cinq pays fabriquaient des vaccins, mais les procédés utilisés étaient dépassés et non normalisés. Par ailleurs, peu de recherches pertinentes étaient menées et les produits ne recevaient qu'une reconnaissance internationale négligeable. En 2014, les cinq pays avaient pris des initiatives importantes en matière de développement technologique de vaccins et avaient largement amélioré leur capacité de régulation nationale. L'Afrique du Sud était alors le seul pays du groupe BRICS à ne pas produire complètement des vaccins. L'Afrique du Sud a maintenant amorcé le processus pour relancer sa production de vaccins et pour dépasser l'étape de la simple importation, formulation et conditionnement des vaccins en vrac. On a analysé les variations de prix du secteur public par dose des vaccins sélectionnés, la part du marché mondial représentée par les produits provenant de fabricants spécifiques et l'attractivité des opportunités de partenariat et d'investissement pour les multinationales dans les entreprises du groupe BRICS. Les résultats montrent que les pays du groupe BRICS ont eu un impact majeur sur le prix et la disponibilité des vaccins, et cet impact est attribuable, en grande partie, à la production des fabricants indiens de vaccins. La Chine devrait bientôt avoir un plus grand impact compte tenu du développement attendu des fabricants chinois de vaccins dans un avenir proche. Les réalisations du groupe BRICS dans le domaine du développement de vaccins devraient remodeler le marché mondial des vaccins et accélérer l'accès aux vaccins dans les pays en développement. Le défi est maintenant de transformer ces attentes en actions stratégiques et en résultats concrets.

Brasil, la Federación de Rusia, India, China y Sudáfrica, los países conocidos como BRICS, han hecho progresos considerables en la producción, regulación y desarrollo de vacunas en los últimos 20 años. En 1993, los cinco países ya producían vacunas, pero los procesos empleados para ello estaban anticuados y sin normalizar, había poca investigación relevante y un reconocimiento internacional mínimo de sus productos. En 2014, los cinco países contaban con iniciativas sólidas para el desarrollo de la tecnología relacionada con las vacunas y habían mejorado en gran medida su capacidad normativa nacional. Sudáfrica fue el único de los BRICS que no fabricaba vacunas en su totalidad. En la actualidad, dicho país se encuentra en proceso de restablecer su propia producción de vacunas e ir más allá de la simple importación, formulación y llenado de lotes de vacunas. Se han analizado los cambios en los precios por dosis de vacunas seleccionadas del sector público, la cuota de mercado mundial de productos de fabricantes específicos y el atractivo para las empresas multinacionales de la asociación y las oportunidades de inversión en empresas de los BRICS. Los resultados indican que los países BRICS han tenido un gran impacto en el precio y la disponibilidad de las vacunas, y que una gran parte de ese impacto se puede atribuir a la producción de vacunas de los fabricantes de India. Se confía en que China tenga pronto un impacto mayor, dada la evolución prevista de los fabricantes de vacunas chinos en el futuro cercano. Se espera que los logros de los BRICS en el campo del desarrollo de vacunas remodelen el mercado mundial de las vacunas y aceleren el acceso a las mismas en el mundo en desarrollo. El desafío consiste en convertir estas expectativas en actuaciones estratégicas y resultados prácticos.

Tools and approaches to ensure quality of vaccines throughout the cold chain.

The Expanded Program on Immunization was designed 40 years ago for two types of vaccines: those that are heat stable but freeze sensitive and those that are stable to freezing but heat labile. A cold chain was developed for transport and storage of such vaccines and established in all countries, despite limited access to resources and electricity in the poorest areas. However, cold chain problems occur in all countries. Recent changes to vaccines and vaccine handling include development and introduction of new vaccines with a wide range of characteristics, improvement of heat stability of several basic vaccines, observation of vaccine freezing as a real threat, development of regulatory pathways for both vaccine development and the supply chain, and emergence of new temperature monitoring devices that can pinpoint and avoid problems. With such tools, public health groups have now encouraged development of vaccines labeled for use in flexible cold chains and these tools should be considered for future systems.

Global support for new vaccine implementation in middle-income countries.

Middle-income countries (MICs) as a group are not only characterized by a wide range of gross national income (GNI) per capita (US $1026 to $12,475), but also by diversity in size, geography, governance, and infrastructure. They include the largest and smallest countries of the world-including 16 landlocked developing countries, 27 small island developing states, and 17 least developed countries-and have a significant diversity in burden of vaccine-preventable diseases. Given the growth in the number of MICs and their considerable domestic income disparities, they are now home to the greatest proportion of the world's poor, having more inhabitants below the poverty line than low-income countries (LICs). However, they have little or no access to external funding for the implementation of new vaccines, nor are they benefiting from an enabling global environment. The MICs are thus not sustainably introducing new life-saving vaccines at the same rate as donor-funded LICs or wealthier countries. The global community, through World Health Assembly resolutions and the inclusion of MIC issues in several recent studies and important documents-including the Global Vaccine Action Plan (GVAP) for the Decade of Vaccines-has acknowledged the sub-optimal situations in some MICs and is actively seeking to enhance the situation by expanding support to these countries. This report documents some of the activities already going on in a subset of MICs, including strengthening of national regulatory authorities and national immunization technical advisory groups, and development of comprehensive multi-year plans. However, some additional tools developed for LICs could prove useful to MICs and thus should be adapted for use by them. In addition, new approaches need to be developed to support MIC-specific needs. It is clear that no one solution will address the needs of this diverse group. We suggest tailored interventions in the four categories of evidence and capacity-building, policy and advocacy, financing, and procurement and supply chain. For MICs to have comparable rates of introduction as other wealthier countries and to contribute to the global fight against vaccine-preventable diseases, global partners must implement a coordinated and pragmatic intervention strategy in accord with their competitive advantage. This will require political will, joint planning, and additional modest funding.

WHO policy development processes for a new vaccine: case study of malaria vaccines.

BACKGROUND: Recommendations from the World Health Organization (WHO) are crucial to inform developing country decisions to use, or not, a new intervention. This article analysed the WHO policy development process to predict its course for a malaria vaccine. METHODS: The decision-making processes for one malaria intervention and four vaccines were classified through (1) consultations with staff and expert advisors to WHO's Global Malaria Programme (GMP) and Immunization, Vaccines and Biologicals Department (IVB); (2) analysis of the procedures and recommendations of the major policy-making bodies of these groups; (3) interviews with staff of partnerships working toward new vaccine availability; and (4) review and analyses of evidence informing key policy decisions. CASE DESCRIPTION: WHO policy formulation related to use of intermittent preventive treatment in infancy (IPTi) and the following vaccine interventions: Haemophilus influenzae type b conjugate vaccine (Hib), pneumococcal conjugate vaccine (PCV), rotavirus vaccine (RV), and human papillomavirus vaccine (HPV), five interventions which had relatively recently been through systematic WHO policy development processes as currently constituted, was analysed. Required information was categorized in three areas defined by a recent WHO publication on development of guidelines: safety and efficacy in relevant populations, implications for costs and population health, and localization of data to specific epidemiological situations. DISCUSSION AND EVALUATION: Data needs for a malaria vaccine include safety; the demonstration of efficacy in a range of epidemiological settings in the context of other malaria prevention interventions; and information on potential rebound in which disease increases subsequent to the intervention. In addition, a malaria vaccine would require attention to additional factors, such as costs and cost-effectiveness, supply and demand, impact of use on other interventions, and distribution issues. CONCLUSIONS: Although policy issues may be more complex for future vaccines, the lead-time between the date of product regulatory approval and a recommendation for its use in developing countries is decreasing. This study presents approaches to define in advance core data needs to support evidence-based decisions, to further decrease this lead-time, accelerating the availability of a malaria vaccine. Specific policy areas for which information should be collected are defined, including studying its use within the context of other malaria interventions.

The role of emerging manufacturers in access to innovative vaccines of public health importance.

The role of developing country manufacturers in assuring global access to innovative vaccines was compared to the situation in 2005. These producers now supply over 60% of traditional vaccines doses globally and an increasing value (up to 15% in 2007) of innovative products. More suppliers are now strong players in global market, and an even larger group has potential to do so. These manufacturers are not a homogeneous group and most of them are now at a crossroads. Decisions made by their management and governments as well as by the international community will have a large impact on their existence and future and their ability to manufacture innovative vaccines at affordable prices.

Reaching international GMP standards for vaccine production: challenges for developing countries.

Standards for vaccine production have been increasing at a rapid rate. Current standards of good manufacturing practice (GMP) had been thought to be out of the reach of developing country vaccine producers, many of whom are in the public sector, overseen by unvalidated national regulatory authorities (NRAs). With the advent of the GMP regulations in 1963 and their application to vaccine production, even many industrialized country manufacturers with stringent NRA oversight had difficulties. This article assesses the ability of developing country manufacturers to meet GMP by the only currently available global indicator: WHO prequalification. As recently as 1996, no developing country NRA was considered able to enforce GMP compliance. That number increased to four in 2002 and six in 2006, with a concomitant increase in the number of manufacturers considered to be operating to GMP standards. Examples of the difficulties faced by manufacturers in achieving this are given, as well as implications for the future vaccine market.

Strategies for financial sustainability of immunization programs: a review of the strategies from 50 national immunization program financial sustainability plans.

Financial sustainability plans (FSPs) were developed by over 50 of the world's poorest countries receiving funding support from the Global Alliance for Vaccines and Immunization (GAVI) to introduce new and underused vaccines, injection safety and immunization service support between 2000 and 2006. These plans were analysed with respect to the strategies selected to promote financial sustainability, allowing classification of FSP strategies in three areas: (1) mobilizing additional resources, (2) increasing the reliability of resources, and (3) improving program efficiency. Despite some country successes and the magnitude of planned financial sustainability strategies, huge funding gaps remain for these countries due to the initial underlying assumptions of the GAVI and financial sustainability plan model.

The GO License: only part of the solution.

The Generic Open (GO) License is a proposal to make patents more accessible for vaccines and drugs in low- and middle-income countries. However, for some health-related products, such as vaccines, intellectual property is frequently not the primary constraint. Technical know-how and assurance of a viable market built on reliable demand at prices that cover costs are the most critical factors for vaccine access. Together with innovative efforts to reduce product development risks and costs and to assure credible markets at profitable prices, the GO License may yet play a role in assuring access for drugs and vaccines for poor countries.

The GAVI Financing Task Force: one model of partner collaboration.

The Global Alliance for Vaccines and Immunization, now called the GAVI Alliance, was launched in 2000 as a coalition of partners, including countries, international organizations, bilateral donors, the vaccine production industry, and nongovernmental organizations; most activities were to be implemented through these partner organizations. Four task forces were established at the outset to define issues relevant to GAVI Alliance goals and to recommend actions. This paper describes the innovations and outputs of the Financing Task Force (FTF), which worked in three areas: country support to sustainably finance vaccines and immunization programs in the context of introducing new vaccines; vaccine supply and demand issues as they impact vaccine choice, production costs and price/dose; innovative financing mechanisms for vaccines and immunization programs through, for example, capital markets. This analysis particularly focuses on the FTF's work on financial sustainability. Through its partnership, the FIF was able to leverage organizational change in its participating organizations, in the countries supported by the GAVI Alliance, and in the policies of GAVI itself. These achievements, along with areas where the desired outcome was not achieved, are summarized with lessons that may be useful to other multi-partner health alliances.

Access to vaccine technologies in developing countries: Brazil and India.

This study, conducted by visits, interviews, and literature search, analyzes how vaccine manufacturers in Brazil and India access technologies for innovative vaccines: through collaborations with academia and research institutions, technology transfer agreements with multinational corporations, public sector, or developing country organizations, or by importation and finishing of bulk products. Each has advantages and disadvantages in terms of speed, market, and ability to independently produce the product. Most manufacturers visited are very concerned about avoiding patent infringement, which might result in undeveloped or delayed products because of a lack of mastery of the patent landscape. Disregarding the patent picture could also threaten the market of a potential product. Although it is too soon to assess the effects of TRIPS on vaccine technology access in Brazil and India, a good understanding of intellectual property management will be useful. A case study on development of a new combination vaccine illustrates these findings.

The impact of globalization on vaccine development and availability.

Globalization is likely to affect many aspects of public health, one of which is vaccine-preventable communicable diseases. Important forces include increased funding initiatives supporting immunization at the global level; regulatory harmonization; widespread intellectual property rights provisions through the World Trade Organization agreements; the emergence of developing-country manufacturers as major players in vaccine supply; and the appearance of new communicable disease threats, including those potentially linked to bioterrorism. All of these forces can affect, either positively and negatively, the development and availability of vaccines. Harnessing these will be a challenge for policymakers and immunization stakeholders.

Managing the effect of TRIPS on availability of priority vaccines.

The stated purpose of intellectual property protection is to stimulate innovation. The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) requires all Members of the World Trade Organization (WTO) to enact national laws conferring minimum standards of intellectual property protection by certain deadlines. Critics of the Agreement fear that such action is inconsistent with ensuring access to medicines in the developing world. A WHO convened meeting on intellectual property rights and vaccines in developing countries, on which this paper is based, found no evidence that TRIPS has stimulated innovation in developing market vaccine development (where markets are weak) or that protection of intellectual property rights has had a negative effect on access to vaccines. However, access to future vaccines in the developing world could be threatened by compliance with TRIPS. The management of such threats requires adherence of all countries to the Doha Declaration on TRIPS, and the protections guaranteed by the Agreement itself, vigilance on TRIPS-plus elements of free trade agreements, developing frameworks for licensing and technology transfer, and promoting innovative vaccine development in developing countries. The role of international organizations in defining best practices, dissemination of information, and monitoring TRIPS impact will be crucial to ensuring optimal access to priority new vaccines for the developing world.

Development of priority vaccines for disease-endemic countries: risk and benefit.

Decisions regarding vaccine regulation and use made by institutions in industrialized countries can have an unintended impact on vaccines' availability in disease-endemic countries. However, regulatory and programmatic decision making by such countries, taking into consideration local risks and benefits, requires adequate resources, both human and financial. Such differing risk-benefit determinations between industrialized and disease-endemic countries will increase product divergence. We propose a single universal standard for risk assessment, based on maximizing net benefit, and an action plan to improve access to priority vaccines through a more robust determination of risk and benefit.

Regulation of vaccines: strengthening the science base.

This paper aims to review the history of development of vaccine regulatory approaches, to assess practices that may be barriers to access to innovative products, and to suggest possible approaches to address these practices. Despite the appearance of new vaccines in the past few years, many vaccines are based on old technologies, and are still subject to regulatory practices devised many years ago. Vaccine regulation began with a foundation on vaccine testing, and only in response to tragedies associated with vaccine use did new concepts begin to be defined. Vaccine regulation now includes a range of functions that cover the entire continuum of vaccine development and use. However, some regulatory practices, such as the continuing dependence on outdated animal tests, have not kept pace with these changes. Other practices, such as the continual raising of the standard of Good Manufacturing Practice (GMP) compliance, or the move to increasingly larger phase 3 clinical trials, appear to be based more on perceived risks than on firm scientific principles. The future of effective regulation for vaccines that will allow innovation while protecting the public health must be based on three guiding principles: a firm science base for policies and decisions, a risk-based approach to implementation of regulatory oversight, and support for regulatory research to inform these activities. These should be implemented in a setting of international harmonization.

Regulatory pathways for vaccines for developing countries.

Vaccines that are designed for use only in developing countries face regulatory hurdles that may restrict their use. There are two primary reasons for this: most regulatory authorities are set up to address regulation of products for use only within their jurisdictions and regulatory authorities in developing countries traditionally have been considered weak. Some options for regulatory pathways for such products have been identified: licensing in the country of manufacture, file review by the European Medicines Evaluation Agency on behalf of WHO, export to a country with a competent national regulatory authority (NRA) that could handle all regulatory functions for the developing country market, shared manufacturing and licensing in a developing country with competent manufacturing and regulatory capacity, and use of a contracted independent entity for global regulatory approval. These options have been evaluated on the basis of five criteria: assurance of all regulatory functions for the life of the product, appropriateness of epidemiological assessment, applicability to products no longer used in the domestic market of the manufacturing country, reduction of regulatory risk for the manufacturer, and existing rules and regulations for implementation. No one option satisfies all criteria. For all options, national infrastructures (including the underlying regulatory legislative framework, particularly to formulate and implement local evidence-based vaccine policy) must be developed. WHO has led work to develop this capacity with some success. The paper outlines additional areas of action required by the international community to assure development and use of vaccines needed for the developing world.