Improving public health through collaboration in research

International Congress Series 1267 (2004) 7 – 16 www.ics-elsevier.com Improving public health through collaboration in research N. Robert Bergquist * Ingerod 407, 454 94 Brastad, Sweden Abstract. The most pressing public health problems are found in the developing countries. Many of them are related not only to endemic tropical diseases such as malaria, schistosomiasis and other parasitic diseases but also to pandemics such as tuberculosis and HIV. Improving this situation is dependent on strengthening the global health research capacity in order to advance self-reliance and prudent use of available resources. Biomedical research is increasingly important both for solving structural public health problems and for fighting specific diseases but it also essential that it is properly conducted. The role of research in the promotion of public health issues was understood early on and an initiative to realize this goal was taken in the mid-1970s which resulted in the creation of the Special Programme for Research and Training in Tropical Diseases (TDR) with funds from the United Nations Development Programme (UNDP), the World Bank, and the World Health Organization (WHO). Originally TDR focused on six target diseases but this number has now increased to 10 and the programme is today a vital research programme in the WHO Communicable Diseases cluster and comprises more than 70 member countries in addition to the founding organizations. Its charter aims at supporting research projects on tropical diseases on a global scale and, in particular, strengthening research capability in this area in the developing countries. An overview of recent progress in this area is presented, emphasising how research can contribute to improved public health in the developing world. D 2004 Elsevier B.V. All rights reserved. Keywords: Public health; Research; Disease control; Tropical disease; Pharmacological industry 1. Introduction Due to its potential to bridge the divide between the rich and the poor modern science and technology are pivotal for the future of public health [1,2]. However, although genomics and associated fields are important for controlling endemic infections, the economic situation in the developing countries also needs to improve if real quality of public health is to be achieved. Shortcomings are not only due to lack of financial means but often also to insufficient understanding of the cause and impact of common diseases coupled with failure to acquire and learn the use of existing tools for their control. * Formerly Basic and Strategic Research, UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland. Tel.: +41-523-43336. E-mail address: [email protected] (N.R. Bergquist). 0531-5131/ D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.01.077 8 N.R. Bergquist / International Congress Series 1267 (2004) 7–16 Interestingly, current thinking sees health as the prerequisite for social development, industrial progress and economic growth in general [3]. Therefore, if the vicious circle of lagging socioeconomic development and deteriorating public health is to be broken, it makes sense to begin by strengthening education and the general health of people. Direct financial support is useful but the long-term strengthening of institutions and people’s own capabilities allow them to influence decisions that facilitate and improve the chances of achieving the required momentum as well as sustainability. Health research should not be seen as an isolated activity but rather as an instrument for generating new information and weaving it together with existing ways and means of improving the situation. It is, in this connection, fundamental to recognize the need for research that is both basic and applied. Knowledge of the sequences and function of genomes is thus becoming an integrated part of the basis for the development of new health interventions. 2. Public health interventions require a research component The focus on genomics is a good example of how research can provide an impetus opening up new opportunities for the development of drugs, vaccines and diagnostics. Apart from providing data central to current public health management, it has ushered in a new emphasis on post-genomic research which will permit further development based on a better understanding of the disease processes. Bioinformatics or computational biology, a necessity for the advancement of both strategic and applied research, is increasingly needed to help in contributing to improve knowledge regarding access, representation and comprehension of biological themes. Social, political and economic inequalities are central to the persistence and spread of disease, while increased international travel has removed the geographical barriers previously preventing its spread between continents. Climate changes and concurrent stresses influence the spatial and temporal distribution of pathogens, vectors, intermediate hosts and reservoirs affecting disease dynamics in unforeseen ways and favouring the emergence of new cross-species diseases. For example, increased livestock/human contact and urbanization create new epidemiological hotspots that can lead to the expansion of a multitude of infections with long-term consequences for vector/human contact and disease transmission. It can be argued that the low priority of health-related research in most disease-endemic countries is the greatest obstacle to progress in this area. Public health measures can contribute to the control of infectious diseases but often fall short of their potential in protecting vulnerable populations. Despite the fact that integrating research in public health activities is the key to success [4,5], the general resistance to change reigns, or the opposite belief, that investments in basic research alone will automatically lead to new tools and their adoption [6], dominates. Either attitude delays progress and the first to suffer are the populations of the third world where medical conditions, infectious diseases in particular, disproportionably affect those who are already marginalized due to low economic status. An extremely small part of all funding spent on health research in the world is devoted to diseases affecting the poor. In the year 2000, the Global Forum for Health in Geneva, Switzerland [7] estimated the figure to be less than 10% and there is no reason to believe that the figure is higher now. The public sector is not powerful enough to make an impact in product development, N.R. Bergquist / International Congress Series 1267 (2004) 7–16 9 while the private sector has little leeway of changing its course due to the huge costs involved. Only a very small minority of promising leads ends up as a marketable drug or vaccine for human use forcing industry to primarily invest in development projects in areas where they can expect to make profits, i.e. the developed, industrialized world. This is amply illustrated by the fact of 1450 new chemotherapeutical agents, introduced between 1972 and 1997, only 13 were for treating the neglected infectious diseases [8,9]. 3. A programme for health research The decision to establish the Special Programme for Research and Training in Tropical Diseases (TDR) in 1975 should be seen against the background of a bare minimum of support being spent on research on the great pandemic tropical diseases. It was made possible by joint funding from the United Nations Development Programme (UNDP), the World Bank, and the World Health Organization (WHO). TDR is today a vital research programme in the WHO Communicable Diseases cluster which has attracted more than 70 member countries in addition to the founding organizations. It has grown vigorously over the last few years and currently employs close to 100 people with an annual budget exceeding US$ 30 million. After the recent addition of tuberculosis and dengue fever to the original target diseases, research on many aspects of 10 different diseases is promoted. Disease-oriented research is mixed with trans-disease activities with the aim of gaining a better understanding of the implications of globalization and changing social, political and civil structures for health equity. The TDR study spectrum stretches from emerging and still uncontrolled diseases, over diseases where a control strategy exists but disease burdens persists, to diseases for which effective control strategies and elimination are in a well-advanced stage of planning (Fig. 1). Some diseases, e.g. leprosy, Chagas and onchoceriasis are near elimination as a public health threat, while the control of others has become more of a question of guiding scientists towards the behavioural aspects of them. Still others are in dire need of new drugs and vaccines to secure control. With the understanding that useful progress cannot be achieved, and changes not instituted, without a genuine broad-based approach TDR is forced to share its resources between many diverse research targets. Four main research areas, Basic and Strategic Research (STR), Product Research and Development (PRD), Intervention Development and Implementation Research (IDE), and Research Capability Strengthening (RCS) are led by four team coordinators in collaboration with 10 disease coordinators, one for each disease (Fig. 2). This matrix ensures that each disease receives support for research from idea to implementation and that each step includes training and capability strengthening aspects. The research support provided for genomics over the last few years has opened an avenue for developing countries to drive a genomics revolution of their own. An important milestone toward controlling the transmission of malaria was achieved in 2002 through the completion of the Anopheles gambiae genome project. Thus, the whole genome sequence of main vector of malaria in sub-Saharan Africa has been assembled and annotated. Bioinformatics and applied genomics are used for the identification of new drugs and targets for diagnostics, pathogenesis, vaccine development and understanding the mechanisms at play in emerging drug resistance. Laboratories in many countries are supported to collaborate on research on defence systems focusing on the genes responsible for 10 N.R. Bergquist / International Congress Series 1267 (2004) 7–16 Fig. 1. After the addtion of dengue fever and tuberculosis TDR divides its resources between 10 ‘‘target disease’’. refractoriness. This work is sometimes straightforward but more often complicated. For example, the tsetse fly vector has typically five chromosome pairs but work on this genome is complex since different species can have different chromosome numbers. The network-based systematic analysis of gene function in Leishmania, on the other hand, has garnered early successes leading to the creation of other genome research networks such as those of Trypanosoma, Schistosoma and Filaria to be created in several advanced third Fig. 2. TDR’s current ‘‘grid structure’’ makes sure that different research aspects of the ten diseases are supported. N.R. Bergquist / International Congress Series 1267 (2004) 7–16 11 world countries. These networks have not only been instrumental in moving science ahead but also have been able to provide local training in this area of cutting-edge research. Today, these networks are themselves supporting developments in applied genomics and, through courses and technology transfer, encourage scientists to develop increased bioinformatics capabilities. The first train-the-trainers workshop was held at the Foundation Oswaldo Cruz (FIOCRUZ) research institute in Brazil. This was an international course which marked the initiation of a creation of a multi-disciplinary and international network for bioinformatics applied to pathogen-oriented genome research. It has successfully promoted self-reliance in this important area and produced a high number of trained researchers from disease-endemic countries. 4. The potential of partnerships in promotion of health Patients with neglected, tropical diseases have benefited from the development of public – private partnerships for drug development. The focus on such collaborative production of drugs brings advantages for resource-poor environments resulting in a unique engagement in the health-related problems of disease-endemic countries [10]. By forming a platform from which partnerships with industry can be developed, a number of new drugs have been created during the last few years. Characterization and profiling of the new products required has been helped by TDR being a WHO-based programme. The first serious collaboration with industry situation came about through the observation that ivermectin, a drug used to treat heart worm infection in dogs, was effective for the treatment of human onchocerciasis (river blindness). TDR worked with the US pharmaceutical corporation Merck developing the product that was finally registered for human use in 1989. Merck has since made the commitment to produce the drug free of charge for the endemic areas in Africa for as long as it is needed. This commitment has become the cornerstone of the successful control programme for onchocerciasis that has been joined by numerous governments and non-governmental agencies. Thanks to this programme millions of children can grow up without the risk of infection by this filarial worm which leads to complete blindness for the majority if not treated. The disappearance of infection has also freed about 25 million hectares of fertile riverside land for resettlement and the additional agricultural production has proved sufficient to feed 17 million people. Another partnership, this time between TDR and GlaxoSmithKline in the United Kingdom, was formed to develop a new anti-malarial drug [11]. Malaria causes more than 1 million deaths per year, mainly among children, making it a priority to develop a new safe and effective drug [12]. Still another project aims to develop fixed-dose artemisinin combinations for malaria through collaboration involving TDR, a specialized international organization, i.e. the Medicines for Malaria Venture (MMV) and two different pharmaceutical company partners [10]. Interestingly, artemether has also effect against the larval stages of Schistosoma [13] and seven large-scale clinical trials were carried out in China between 1994 and 1996 which demonstrated that artemether and derivatives of this drug can reach 100% protection (average 85%) against Schistosoma japonicum [14]. In collaboration with Kunming Pharmaceutical, China, successful clinical trials against the two other important species of this parasite, Schistosoma mansoni and Schistosoma haematobium, have been carried out in Africa [15,16]. 12 N.R. Bergquist / International Congress Series 1267 (2004) 7–16 A new oral drug against leishmaniasis has been developed in partnership with Zentaris, a small German pharmaceutical company [17]. This drug, miltefosine, is currently in Phase IV clinical trials, while Phase III studies with another new drug against this disease, paromomycin, is about to start in partnership with the One World Health Institute [10]. For African trypanosomiasis, or sleeping sickness, we are still relying on suramin and melarsoprol which are both highly toxic drugs developed decades ago. The most recent addition to the arsenal against African trypanosomiasis came in 1991, with the registration of an intravenous formulation of eflornithine. This drug, developed by Marion Merrell Dow, now Aventis, after negotiations with TDR, is highly effective against the later stages of the disease. However, more research is needed since it is only active against one of the species that causes human African trypanosomiasis and it is also too expensive for general use. Because clinical studies of drugs against tropical diseases must take place in developing countries, local clinical researchers normally participate. Each study requires extensive preparation and training in the conduction of clinical studies. During the past several years, networks of clinical researchers and clinical trial monitors have been trained in good clinical practice. The clinical studies undertaken in partnership with Zentaris took place in the Indian State of Bihar, where almost all outbreaks of visceral leishmaniasis in India occur. Thanks to these studies a network of local expertise on drug development has been created which has had major benefits for the later implementation of new drugs [18]. Following these interventions the Rajendra Memorial Institute in Patna has become a recognized centre of excellence for clinical studies. Since the start of TDR, several organizations with similar goals have been initiated and slowly, but unmistakably, the signs of change are appearing. Health issues in the developing countries have started to move from an area of ignorance and neglect to a more prominent standing on the political agenda. Evidence of this can be seen in the strengthened management of existing initiatives which has resulted in tangible improvements of public health [19,20], while specific diseases are starting to be tackled by new public –private partnerships. Examples include the recently established Global Fund to Fight AIDS, Tuberculosis and Malaria (www.globalfundatm.org), the Medicines for Malaria Venture (www.mmv.org) and the Global Alliance for TB Drug Development (www.tballiance.org) established in 1999 and 2000, respectively. Another recent initiative attracting resources to drug development for tropical diseases is the Drugs for Neglected Diseases Initiative led by Médecins Sans Frontières (www.accessmedmsf.org). 5. Social and economic research Only by embracing a true trans-disciplinary approach can we intervene successfully. For example, when irrigation schemes or dam construction alter the epidemiology of schistosomiasis or filariasis, the views of health workers as well as of policymakers should be taken into account. When recurrent drug stock-outs characterize a tuberculosis control programme, patient attitudes and practices may be of less relevance to the emergence of drug resistance than fluctuating drug prices, tariffs, and poor drug quality. When poor blood-screening practices lead to an increased prevalence of Chagas disease the anthropology of blood banking is called for. The emergence of new strains of infectious agents resistant to our therapeutic arsenal could be thought of as classic biosocial problems. There N.R. Bergquist / International Congress Series 1267 (2004) 7–16 13 is simply no way to understand the dynamics of emerging drug resistance without an understanding of both microbial and human behaviour. Biological research may provide needed tools for disease control but elucidation of political and behavioural factors is the key to effective infectious disease control programmes, product development and implementation. Research with regard to the impact of broader reforms in the overall organization of health care systems has provided insights regarding the forces preventing governments from taking the actions necessary for reform. In its annual report, TDR summarizes recent findings in this area [21]. For example, serious implementation problems emerged in Columbia despite radical overhaul of the entire system of health financing for the poor including substantial increases in resources and, in India, research on hospital accreditation has revealed what seems to be a real willingness to participate in a voluntary accreditation system but large gaps remain in the access to health care between rich and poor. Several interesting findings are reported from China: Increasing costs and breakdown of the state-operated insurance system has widened the gaps in health access between rural and urban and high and low income groups.  Economic and social barriers leave the growing migrant populations without adequate prenatal care leading to a poorer pregnancy outcome compared with permanent residents.  Public hospitals increasingly function as private enterprises making it impossible for many people to afford medical care.  A South African study points to the rise in neglected STD infections showing that local doctors tend to prescribe less expensive and less convenient treatment regimens to poor patients. A similar issue in the different world of rural health centres is reported from Uganda. There, like in China, the central government has urged fee exemptions to protect the poor but has not provided funding to pay for lost revenue which has stymied the implementation of the initiative on the local level. In Laos it is reported that user fees and bureaucracy in public facilities have led to a growth of the private health care sector where now both the rich and the poor get most of their care; the rich mainly from private clinics and the poor from pharmacies selling drugs without examination. However, with regard to the impact of specific changes in health care financing on expenditures and service utilization, several new results have emerged. Examples include: a successful pharmaceutical cost-containment policy for hospitals in Shanghai; a new policy for hospital financing in Indonesia; and  a shift of health care utilization from hospitals towards health centres in Zambia.   There is much evidence that armed conflict and infectious diseases are intimately linked. The interface of the TDR diseases with conflict and other crises is therefore an important priority. It has been suggested that 65% of infectious disease epidemics occur in unstable countries, while direct war-related mortality ranks in the top 12 most common causes of death worldwide and is projected to become the 8th most common cause of death by 2020. Displaced people typically experience high mortality, especially in the period immediately following their displacement and infectious diseases and nutritional disadvantage are the 14 N.R. Bergquist / International Congress Series 1267 (2004) 7–16 key factors. In conflict settings, the quantity and quality of health care available is usually greatly reduced; vector control programmes, outreach services, training, referral, and drugs distribution are all typically impeded. Findings in Ethiopia and Mozambique showed that epidemics of malaria were associated with deterioration in disease control activities. In Nicaragua, an increased risk of malaria was associated with war-related population and troop movements, inability to carry out timely disease control activities and shortages of health personnel. Paradoxically, however, conflict situations can also have a positive impact on societies and health systems which has been demonstrated in Nicaragua, Mozambique, Viet Nam, Eritrea and Tigray. In the popular conflict against the Ethiopian ruling class, the Derg, community-based political movements in Eritrea and Tigray engaged strongly in building community structures for participation and decision-making, facilitated the development of multi-sectoral health promotion strategies, and identified innovative community-financing systems. To address the most common problems in this area an agenda should be established for research on conflict and health systems aiming to review how infectious diseases and conflict interact and how communities and health systems respond. Also needed are access to country profiles focusing on conflict with regard to infectious diseases, health systems and community responses and, perhaps most important, cohorts of enthused research activists who are keen to explore, understand and promote improved policy responses to infectious diseases and conflict. A 2-year prospective study of costs and performance of the malaria control programme in two counties with endemic Plasmodium vivax malaria in Henan Province, China showed great variations in case management. Of 12,325 suspected malaria cases, only 4545 (37%) got some form of treatment and as little as 131 (1%) received the excellent care all are entitled to. The remainder 7780 patients (63%) were dealt with in a clearly inadequate manner. The researchers concluded that efforts should be made to improve the efficiency of case management if malaria eradication is to be achieved and that good management requires continued government investment in malaria control. Case management would improve if village doctors began anti-malaria treatment more promptly (within 3 days of diagnosis) and continued treatment longer (for at least 3 days). This can actually be achieved without increased government investment since other aspects of case management, such as rapid patient access to care and choice of drug, are already operating well. Decreased government spending would increase the costs for the suspected cases and their families and delay treatment. Such a development would increase the risk of recrudescent transmission and ultimate breakdown of control as has occurred in the endemic countries of South Asia but so far not in China. Social, economic, political, behavioural, and health system factors all affect, and are affected by, disease patterns and disease control efforts. Social research to elucidate these factors is the key to effective infectious disease control programmes, product development and implementation. TDR promotes and manages social research and training on a number of critical issues related to tropical disease control and international public health, particularly focusing on: inequality of access to health care; policy processes;  gender-sensitive interventions;   N.R. Bergquist / International Congress Series 1267 (2004) 7–16   15 conflict and infectious diseases; and ethics of social research and biotechnology. 6. Health sector reform On a worldwide scale, parasitic infections and other diseases disproportionately affect populations living in poverty. The last decade has witnessed a series of government-level reforms aimed at improving the equity of access to care and thus the general health status of all citizens. The current expanded support of research into health sector reform in the developing world grew out of a set of ideas, developed and initiated in the mid-1990s which was, to a large part, sponsored by the Norwegian government. TDR takes an active interest in this area since it feels that health management in general has a strong impact on its overall approach to improving the lot of those at risk for, and very often infected by, the common infectious, endemic diseases of the developing world. It has been shown that health legislation alone is seldom capable of creating true community participation in settings with a limited history of democratic participation. In addition, there is little correspondence between official policy and reality when distinctions between public and private health care disappear. By bringing a broad array of political and social-science methodologies to bear on the problem, TDR seeks to address the chief causes of morbidity and mortality among the world’s poorest. 7. Conclusions The TDR example has shown that partnerships between the public and private sectors constitute the way forward with respect to provision of new, effective medicines for neglected diseases affecting the poor. Partnerships can also be useful for more general public health improvements but here a true trans-disciplinary approach is the key to successful intervention. Important progress can be made with relatively modest financial contributions as long as support of initiated projects continues over a long period of time. This type of collaboration is also capable of a positive effect on diseases of limited commercial interest and sustained collaboration can have a dramatic effect on social and economic development. References [1] P.A. Singer, A.S. Daar, Harnessing genomics and biotechnology to improve global health equity, Science 294 (5550) (2001) 2289 – 2290. [2] A.S. Daar, H. Thorsteinsdottir, D.K. Martin, A.C. Smith, S. Nast, P.A. Singer, Top ten biotechnologies for improving health in developing countries, Nat. Genet. 32 (2) (2002) 229 – 232. [3] J. Sachs, The essential ingredient, New Sci. 175 (2002) 52 – 55. [4] D.A. Henderson, Eradication: lessons from the past, Bull. 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