PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Drugs and Diagnostic Innovation in the Developing World: A Review and Call For Debate by Marc Twagirumukiza, MD, PhD Fellow Background and Objectives Recent international and regional inter-governmental meeting reports have highlighted the link between health, innovation and economic development1-3. Expenditure on health and health research and development, by both the public and private sector, is now increasingly seen as an investment in economic prosperity1;4;5. But the United nation (UN)5 reports that important gaps remain in delivering on the global commitments in the areas of access to new technologies and to affordable essential medicines. In the countdown to 2015, urgent responses are needed to bridge the existing implementation gaps to make good on the promises made to achieve the Millennium Development Goals5;6. The driving force for drug discovery and development by pharmaceutical firms has been the foreseeable profit from drug sales5. Since most infectious diseases prevail in developing countries and the fact that people living in these countries have poor purchasing power, the market for such drugs are unattractive to these firms2. Thus, there has been reluctance for the pharmaceutical companies to engage in the development of drugs addressing diseases that mainly affect developing countries. Even if the limited research activities to discover new effective and cheap drugs are in progress in the disease endemic countries, it is not yet possible to fully develop leads and drug candidates from natural products; hence people in these countries continue to rely on traditional medicines. Poor economies7 and technological capabilities, and a lack of human resources and good management in these countries are the major constraints to progress in research and development work for new drugs. Focusing on developing worlds, the lack of market incentives to drive health product Research and Development (R&D), fragile health services infrastructure, as well as weak regulatory environments are partly blamed for the high burden of infectious tropical diseases in developing countries especially in Africa, Latin America, and some Asian countries2. The increasing global awareness about this inequity has resulted in the availability of new funding from governments and philanthropic agencies to support R&D efforts that target diseases that disproportionately affect the developing world. This has resulted in a much needed boost in product development activities for some diseases, especially through public-private partnerships. However, many in developing countries believe that the only way the availability of new affordable drugs, diagnostics, and vaccines for these diseases can be ensured and sustained in the long term, is through committed investments in R&D, manufacturing and distribution within these countries. This work is aimed to figure out the current situation and development in the area of drug discovery and diagnostic innovation in the developing countries, and to initiate a debate about challenges and opportunities in this field. Methodologies This work is a literature review. The literature search includes all academic/scholar published papers in the field, World Bank reports and Millennium Development Goals reports (MDGs). The regional meeting proceedings addressing the issue of drug discovery and diagnostic innovation were also consulted, such as: The African Network for Drugs and Diagnostics Innovation (ANDI) documents3, "Asia/Africa Center for Drug Discovery" reports developed by Meiji Pharmaceutical University, and the "Asia and Africa Science Platform Program" initiated by the Japan Society for the Promotion of Science (JSPS). Findings and Discussions Research and Development on an International Level Drug Discovery and Diagnostic Innovation, as well as all technology innovations, are the outcome of an R&D activity. Normally R&D activities are conducted by specialized units or centers belonging to companies, universities and state agencies. R&D is therefore linked to the economy and development of the country. The Organization for Economic Cooperation and Development (OECD)8 reports that in 2006, the world's four largest spenders of R&D were the United States (US $343B), the European Union (EU) (US $231B), Japan (US $130B) and China (US $115B). In terms of percentage of GDP, the order of these particular spenders for 2006 was China (US $115B of US $2,668B GDP), Japan, United States, and the EU with approximate percentages of 4.3, 3.2, 2.6, and 1.8 respectively. The overall top spenders in terms of percentage of GDP were China, Sweden, Finland, Japan, South Korea, Switzerland, Iceland, and the United States, followed by 9 other countries, and then the EU. The 2008 report shows similar trends (Figure 1)8. Figure 1. Gross domestic expenditure on R&D: As a percentage of GDP, 2008  Source: OECD Factbook 2008: Economic, Environmental and Social Statistics - ISBN 92-64-04054-4 - Copyright © OECD 20088 Involved Organizations and a Current Picture of Drug Discovery and Diagnostic Innovation in the Developing World Networking among research laboratories across various sectors (industrial, academic and the government) has long been recognized as a valuable strategy to optimize research productivity5;9. In the developed nations, this strategy has yielded high levels of sustained innovation5. In developing countries, pharmaceutical companies are concentrated in close proximity to academic centers of excellence. Therefore industry draws from the basic research of the academia and translates them into treatment options with the government facilitating this process. According to one estimate, in the year 1993-94, about 80% of the industrial patents (pharmaceutical) in the USA cited publicly funded research10. There is a need to evolve frameworks that will facilitate and promote such synergistic networking in the developing world as well. In Asia (apart China), Drug Discovery and Diagnostic Innovation is more healthy than in Africa or Latin America10. This is mainly due to disparities in the level of development seen in some countries like India, Pakistan, Singapore, Thailand and others. R&D has progressed more in India since 1970 largely due to the revised patent law that permitted manufacturing & marketing of patented novel chemical entities by alternative, non-infringing processes. The industry might have, in all likelihood, evolved into a research-driven industry over time10. However, the formation of the World Trade Organization (WTO) in 1995 and the obligation of the member countries to comply with the Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS) provisions have only hastened this business eventuality10;11. Some of the progressive Indian companies pioneered this transition in the last decade by initiating internal drug discovery programs. The effort of such enterprising companies has yielded some initial success. Still on the Asian continent, some organisations were created to coordinate effort in the field, for instance the "Asia/Africa Center for Drug Discovery" initiated by Meiji Pharmaceutical University (Japan) for the purpose of educating and training internationally active researchers and pharmacists of drug discovery. In the same trend the "Asia and Africa Science Platform Program" was established by an independent administrative institution, the Japan Society for the Promotion of Science (JSPS), to establish core research institutions concerned with relevant fields within Asian and African countries to foster young researchers by building sustainable relations with core institutions from Asia and Africa. On the African continent3, over the past 5 years or more, the concept of an indigenous African institution focused on health product research and innovation has been raised and discussed. Several reports have highlighted the need for African governments and international agencies to support the transition of African science from fragmented and isolated activities to more coordinated and integrated R&D efforts across the continent. However, a determination to move on has been promoted through the Africa's New Partnership for Africa's Development (NEPAD) text2;3 which stipulates that: "Scientific and technological capacity for health cannot, thus, be reduced to equipment, funding and number of health scientists and technicians. It is the configuration of skills, policies, organizations, non-human resources, and overall context to generate, procure and apply scientific knowledge and related technological innovation to identify and solve specific health problems. The capacity is built through interactive processes of creating, mobilizing, using, enhancing or upgrading, and converting skills/expertise, institutions and contexts."3 Despite this promotion (and more closely linked to the poverty situation of African countries), no one African country or institution has demonstrated the capacity to move from basic research to discovery of a new chemical entity to registration and commercialization of a single new drug product2. However, consultations with many African scientists and experts both at home and in the diaspora suggest that this can be achieved through a strategic mechanism to support relevant continent-wide activities in a coordinated and structured manner3. This has led to the conceptualization of the African Network for Drugs and Diagnostics Innovation (ANDI) as a platform to help support African institutions to participate in discovering, developing and manufacturing the health products they need the most. ANDI held its first successful meeting in Abuja (Nigeria) in 2008. Within the particular context of sub-Saharan Africa, possibilities exist to build up a sustainable African-led R&D innovation by strengthening and utilizing existing capacity and infrastructure to promote collaborative efforts directed towards sustained delivery of affordable health products including those based on natural products and traditional medicines. As individual African countries are considered, South Africa is incontestably the top in drug discovery, development and diagnostic innovation. This is mainly linked to the healthy economy, technology capacity and overall development; other countries are also on the list like Kenya and Cameroon, among others. Still on the continent, the Kenya Medical Research Institute (KEMRI) is among emerging institutions in R&D in sub-Saharan Africa3. Research and Development activities are organized into four programmes: Infectious Diseases; Parasitic Diseases; Epidemiology, Public Health and Health Systems Research; and Biotechnology and Non-Communicable Diseases. The Institute has collaborated with various organizations in trying to achieve its research and development objectives. Notably the Centres for Disease Control (CDC), The Wellcome Trust, The Walter Reed Army Project and Japan International Cooperation Agency (JICA) have been instrumental to KEMRI in putting up the research infrastructure. A production facility has been put up with the assistance of JICA that manufactures diagnostic kits on a large scale3. These kits comprise rapid test kits for screening Human Immunodeficiency Virus(HIV), Hepatitis B and C among others. The key challenge facing the Institute is inadequate budgetary support from government for R&D activities. In Africa3, some drugs are under experimental developments, such as: "TDR15087 UCT" (in South Africa), "Nicosan" & "NIPRD AM1" (in Nigeria), Anti-schistosomiasis medicine (in Egypt), "Balembo cough mixture" and "Malarial-5" (in Mali). In addition, diagnostic innovations include immunodiagnostic kits, molecular assays of viral hepatitis and recombinant therapeutic proteins that are being developed in Egypt. All those efforts are mostly jammed by lack of support (financial, technological and human resources)3. In other parts of the third world, such as Asia (mostly in India) and Latin America, other research is directed towards key therapeutics and diagnostic areas, and aims to accelerate drug discovery and development in: Cancer, Cardio-Metabolic, Neurodegeneration, Anti-infectious, Orphan Diseases, Inflammation; Transforming Technologies; Translational Medicine; Next Generation Therapeutics; and R&D Strategies. However, the developing world still stays at the bottom of list in R&D, and the area of infectious disease remains the only domain that reveals interest for scientists in these limited resources settings. Infrastructure Issues Drug discovery and development is a complex, multidisciplinary endeavour and adequate infrastructure is essential for this purpose. Once again this is strictly linked to the individual economy of the country and explains disparities and inequity in the developing world. One point raised is the good will of the governments to invest in research. In fact, since it is extremely challenging for developing world companies to create the entire infrastructure required for this purpose in-house, the governments must facilitate the establishment of common resources that can be used both by academia and industry2. This will avoid unnecessary duplication of resources and will provide ready access to those that need them. In Africa, the research capacity--comprised of the institutional and regulatory frameworks, infrastructure, investment, and sufficiently skilled people to conduct and publish research--varies widely across countries. In a report to the World Bank that ranked countries according to their national investments and productivity in science and technology, South Africa, Egypt, and Mauritius did reasonably well, while the rest of Africa appeared at the bottom of the league table under "scientifically lagging countries."7;12 This generalisation hides the fact that scientifically less advanced countries may have excellent capacity in certain niche areas. Technology Transfer Issues The advances in science and technology have made the drug discovery and development process highly sophisticated5. If genomics and proteomics-based approaches have the potential to yield novel drug targets, combinatorial chemistry and high throughput screening have enhanced the capability to shorten the time taken to discover lead compounds5. Adopting such technologies for drug discovery and development will be very challenging for companies working in the developing world for two reasons. The cost of implementing these state-of-the-art technologies presently is beyond the reach of most companies10. In addition, it will be difficult to find skilled professionals to develop these technologies in developing countries13. Obviously they will rely on foreign experts, but on-field training may be easy and less expensive. In this scope, pharmaceuticals companies present in the developing world may plan their drug discovery programs to leverage on the relatively less expensive approaches of drug discovery. For instance, the analogue approach for discovering novel chemical entities will be guided by known validated targets and well recognized chemical scaffolds for which the clinical proof of principle is already established10. However, as the discovery programs mature over time, companies must judiciously adopt new technologies for pursuing cutting-edge research. This is because it is novel target based research that results in breakthrough therapies for the treatment of disease. Human Resources Drug discovery and development is a knowledge-based endeavor and the availability of quality researchers is crucial for success10. Traditionally many developing countries' researchers have been trained in western countries in science and technology and have better career prospects. Very often these researchers, once they return home, are in quite different activities from what they have been trained for. Few of them keep the link with their mentors or continue research. The lack of a suitable environment for research, career paths and lack of incentives are among the factors leading to these situations. Of course some of those researchers stay in western countries or they continue to look for positions in other parts of the world. It's important to create a suitable environment in developing countries to benefit from all knowledge of trained researchers. In this scope, creating R&D activities in the developing world may contribute to solving the puzzle. Companies that need to start their drug discovery & development in developing countries can benefit from scattered manpower if advertisements are done internationally. Innovation and Intellectual Property One crucial issue in drug discovery, development and diagnostic innovation, is intellectual property. But the good news is that the area is well organized and regulated. Most governments and organizations in developing countries have set up the needed process, and this issue is no longer a barrier to R&D2. In Africa3, governments have contributed greatly to the development of a Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property that was approved through a World Health Assembly resolution in May 2008 (WHA61.21). This has paved the way for a greater focus on supporting developing countries to participate in the discovery, development and delivery of the products they need the most. This resolution builds upon other commitments by African governments such as the NEPAD health targets, the Abuja declaration of March 2006, the Accra declaration on Health Research adopted in June 2006 and the Algerian declaration on Research for Health in the African Region adopted in June 2008. ANDI (African Network for Drugs and Diagnostics Innovation) came at a time3 when various stakeholders were seeking concrete ways to meet these commitments and to promote sustainable product R&D and capacity development in developing countries, especially in Africa12. Challenges and Opportunities Despite the various challenges that the developing countries' pharmaceutical industries face in their effort to evolve into a research-driven industry, the current availability of scientific talent, cost advantages, large patient populations provide a unique competitive edge. Given the size of developing countries' population, a self-reliant healthcare industry is critical to reduce the burden of maintaining its health. Most developing countries, especially in Africa, are nowadays undergoing the demographic transition and industrialisation process2. This period constitutes a good opportunity to encourage at the same time R&D activities and sustain drug discovery and diagnostic innovation. While the pace of this transformation will be contingent upon deploying resources strategically and effectively negotiating the current & future challenges, it can be catalyzed by a collaborative, resilient effort of the government, academia and industry12. Our results show that few, and isolated, product discovery and development activities are ongoing in Africa12. To achieve coherent and sustainable product innovation, greater effort is needed to bring groups working in this area together so they may join forces, share lessons, and explore a more coordinated approach to health R&D and innovation. In the specific area of drugs, our study shows that no one African country or institution has demonstrated the capacity to move from basic research to discovery of a new chemical entity to registration and commercialization of a single new drug product. However, consultations with many experts suggest that this can be achieved through a strategic mechanism to support relevant, continent-wide activities in a coordinated and structured manner. Although the study mainly focused on activities related to drug R&D and traditional medicines, it should be noted that African institutions also have an untapped potential to expand their work in diagnostics development and vaccine research, especially through genomics. Indeed, several African institutions have already been able to discover and commercialize new diagnostic tools. Significant capacity also exists in the areas of basic research, lead identification, clinical trials and marketing. However, the challenge is the lack of sustainable mechanisms to translate findings from basic research into concrete products and to further optimize and commercialize such findings. African hospitals and institutions also have the capacity to undertake clinical trials; however, it is not clear whether most of the clinical centers can yet carry out studies to international Good Clinical Practice (GCP) standards9. Major gaps identified were in the areas of: lead optimization, pre-clinical Good Laboratory Practice (GLP) safety assessment, and raw material processing9. In the area of manufacturing, several companies were identified, but it was not clear whether these firms can manufacture products to international Good Manufacturer Practice (GMP) standards9. In all cases, there is a need for better management and coordination of research and procedures. Several experts interviewed expressed the strong desire for greater emphasis in research to support the use of traditional medicines and better management of local knowledge, including intellectual property9. Conclusions Developing countries have the greatest burden of disease in the world today but little control over the source and supply of medicines most needed by its citizens. Many platforms have been initiated to promote and sustain a world-led R&D innovation through the discovery, development and delivery of affordable new tools for the treatment of diseases in Asia, Africa and Latin America, including those based on traditional medicines and natural products. In summary, initial data from the mapping exercise suggest that: 1) significant gaps in capacity, financing and infrastructure remain. At the same time, ongoing activities and available capacity and infrastructure can be leveraged to support expanded health product R&D innovation work in Africa. 2) In the area of traditional medicines, there remains a need for more systematic research evaluation and validation of the biological activities of traditional medicines. 3) Concerted coordination of fragmented R&D in African activities is urgently needed. 4) Mechanisms to support the management of intellectual property need to be put in place. The implementation of Drug Discovery and Innovation in developing worlds depends on: 1) the prospects for a reasonable profit and 2) the prospects for a productive business environment. Developing nations can either help or hinder the pharmaceutical industry's efforts to exercise social responsibility through various policies and practices. To ensure that companies can make a reasonable profit, developing nations should honor pharmaceutical product patents and adhere to international intellectual property treaties, such as the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement. References
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