Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
3 Generate and Share Knowledge to Address Health Problems Endemic to the Global Poor One of the greatest contributions the United States can offer to the global health campaign is to share Americaâs traditional strengthâthe creation of knowl- edgeâfor the benefit of the global poor. With its extensive expertise in science and research, the synergistic partnership between its public and nongovernmental sectors, and its strong financial commitments, the United States can do much to redress the imbalance in knowledge about high-income-country and low-income- country diseases, conditions, and health systems. The U.S. research commu - nity, in collaboration with its global partners, should leverage its scientific and technical capabilities to study health problems endemic to poor countries, more rigorously evaluate programmatic efforts to improve health, and promote global knowledge networks to enable low- and middle-income-country researchers to improve the health of their own populations. GENERATE KNOWLEDGE TO BENEFIT THE GLOBAL POOR As previously discussed, progress in global health over the last half-century has been remarkable and can mostly be attributed to the creation, dissemination, and adoption of novel interventions to improve health. In the public mind, scien - tific innovation to improve global health is often associated with the discovery of exciting medical tools such as vaccines or pharmaceuticals. In reality, however, such innovation also extends to activities that allow these tools to be utilized successfully. These include novel public health programs and healthcare delivery strategies, as well as population-based measures such as innovative epidemiologi- cal surveillance models to track disease within communities. Indeed, most public health advances are the result of a comprehensive
0 THE U.S. COMMITMENT TO GLOBAL HEALTH research strategy that incorporates a variety of tools and interventions spanning prevention, diagnosis, and treatment. The recent eradication of smallpox provides a concrete example of how such a comprehensive strategy dramatically altered disease burden (see Box 3-1). Without a series of research advances, coupled with the political will and financial commitments of national governments, donors, and intergovernmental agencies to invest in this research and its subsequent adoption, it is highly unlikely that smallpox eradication would have succeeded. Today the world faces many enormous challenges in global health, includ- ing halting the spread of HIV, eradicating polio, controlling the use of tobacco products and the onset of chronic noncommunicable diseases, and bringing basic BOX 3-1 Smallpox Eradication Made Possible by a Series of Research Discoveries In 1967, when the World Health Organization (WHO) âlaunched an intensified plan to eradicate smallpox, the ancient scourge threatened 60 percent of the worldâs population, killed every fourth victim, scarred or blinded most survivors, and eluded any form of treatmentâ (WHO, 2009a). Yet why did this commitment to eradicate smallpox come more than 170 years after Edward Jenner had suc- cessfully vaccinated people against the disease in 1798 (Fenner et al., 1988)? Global eradication could become a practical objective only after the develop- ment in the 1950s of a vaccine that did not require cold storage and could be produced on a massive scale (Tucker, 2001). The bifurcated needleâa marvel of simple technology that reduced costs (1,000 needles for only $5)âalso made vaccinating easier, allowing village health workers to be trained in proper delivery in only 15 minutes (Levine, 2008a). Another key element in the eradication effort was the discovery that most effective control could be achieved by selective vac- cination using an innovative surveillance-containment strategy (Foege, 1998), resulting in the interruption of smallpox transmission much sooner than anticipated (Foege et al., 1975). Other research initiatives that enabled the success of smallpox eradication included field studies, which revealed the epidemiology of the disease to be dif- ferent from that previously believed, allowing modification of basic field operations; the discovery that the duration of vaccine efficacy was far longer than was earlier thought, making revaccination efforts much less important; operations research, which facilitated more efficient vaccine delivery and case detection; and studies that conclusively demonstrated there was no animal reservoir to obstruct eradica- tion (Henderson, 1999). Without the follow-on innovation and research to build on the work of Edward Jenner, the eradication of smallpox would not have been feasible. It required the collaborative efforts of researchers working both in laboratories and on the ground to devise a successful containment strategy, and the political will and financial commitment of governments, international organizations, and local communities to adopt the interventions and make eradication a reality.
GENERATE AND SHARE KNOWLEDGE health provisions to the most disadvantaged populations. Like smallpox, todayâs challenges will be met only by comprehensive research and delivery strategies that include the successful development and deployment of novel biomedical tools, new behavioral and public health programs, and impact evaluation to improve our understanding of what works and of how simple and cost-effective interventions can be delivered successfully in even the most resource-deprived settings. Asymmetry in the Creation of Knowledge to Benefit the Global Poor While the creation of knowledge through a comprehensive research strategy is critical for improving health in all countries, the capacity to undertake research varies sharply across countries. Representing only one-fifth of the worldâs popu - lation, high-income countries are home to more than two-thirds of the worldâs researchers, command three-quarters of the gross expenditure on research and development, and originate more than 90 percent of the patents granted in Europe, the United States, and Japan (UNESCO, 2005). High-income countries focus the majority of their research on conditions that affect people within their own bor- ders. As a result, diseases or conditions that are overwhelmingly or exclusively incident in low- and middle-income countries are often neglected (WHO, 2001b), and little energy is devoted to research on how to improve healthcare systems to deliver interventions in these settings. Health research in low- and middle-income countries, especially in the emerging market economies, has increased in recent years. Between 2000 and 2006, the average annual growth rate in the number of patent filings originating from China and India far outstripped that of all reported countries in Europe and North America (WIPO, 2008). Many countries, such as Brazil, Egypt, and South Africa, are now reaping the benefits of decades of investment in educa - tion, health research infrastructure, and manufacturing capacity. These countries are beginning to control endemic diseases and conditions by developing their own interventions, with only modest technical or financial assistance from high- income countries (Morel et al., 2005). For example, Brazilâwhich has the second-highest rate of leprosy in the worldâcontributed more than a quarter of the total funding for research on the disease (Moran et al., 2009). Despite these developments, the U.S. research communityâcomprised of universities, U.S. government agencies, commercial entities, and nonprofit organizationsâcontinues to play a prominent role in health research world- wide. The U.S. research community conducts 50 percent of all health research (Research!America, 2006) and generates almost twice as many scientific publica - tions (32.7 percent of the world total) as low- and middle-income countries com- bined (17.6 percent) (UNESCO, 2005). Over the last decade, this commitment to health research has expanded its focus to include global health issues. A significant portion of global health research is financed, managed, or
THE U.S. COMMITMENT TO GLOBAL HEALTH conducted by American-based universities, public-private product development partnerships (PDPs), and U.S. government agencies that work in partnership with research institutions in low- and middle-income countries. Indeed, the emergence of university research consortiums and global PDPs dedicated to global health demonstrates the extraordinary interest and untapped potential within the U.S. research community to address the health needs of the global poor. By tap- ping more fully into this energy, the United States can further complement the expanded health research efforts of low- and middle-income countries and hasten the discovery and delivery of lifesaving knowledge. Strengthen Knowledge on the Adoption and Dissemination of Existing Interventions Attention is required to address the systemic bottlenecks in health systems and policy making in low- and middle-income countries that keep the full benefits of existing medical and public health knowledge and technologies from being completely realized. Surveys of deaths among children under 5 years of age in 42 low-income countries revealed that while improved technology could potentially avert 22 percent of deaths, improved utilization of existing methods could avert 63 percent of the deaths (Leroy et al., 2007). Although most research focuses on interventionsâ97 percent of the grants awarded by the two largest research funders in recent years were for the devel- opment of new technologies (Leroy et al., 2007)âlittle is known, for example, about the characteristics of delivery strategies that could achieve and maintain high coverage for specific interventions in various epidemiological, health sys - tem, and cultural contexts. Systematic studies that help answer questions about how best to scale up and deliver existing interventions are urgently needed (Bryce et al., 2003; Mills, 2007; Walley et al., 2007). Unfortunately, few programs that deliver specific health interventions undergo the type of rigorous evaluation that improves our understanding of what works and where improvements should be sought. Greater Attention to Health Systems Research Health systems research is âthe production and application of knowledge to improve how societies organize themselves to achieve health goals,â taking into account not only how activities are planned, managed, and financed, but also the roles, perspectives, and interests of different stakeholders. Health systems research is a continuum from rigorous and more generalizable scientific research on major issues facing policy makers, such as how to improve the effectiveness of human resource management, to operational or implementation research, which tends to be highly context-specific (Mills, 2008). The Alliance for Health Policy and Systems Research conducted a biblio -
GENERATE AND SHARE KNOWLEDGE metric survey and found that over a period of 12 years (1991-2003), 1.8 million publications were indexed with at least one major subject heading in the field of health systems research, but only 5 percent of these were concerned with low- and middle-income countries, and an even smaller proportion were produced by low- and middle-income country researchers themselves (Alliance for Health Policy and Systems Research, 2004). While recent years have seen an increasing number of systematic reviews of particular areas of health systems research, in general, they have not yielded information that has dramatically influenced public policy. For example, although several studies have examined the effectiveness of working with private providers to improve equity in health for the poorest indi - viduals, no robust conclusions to influence policy makers can be drawn without more extensive and higher-quality evidence (Patouillard et al., 2007). Health systems research, when of high quality and when conducted through a number of comparative studies in different countries on a particular theme, is a particularly important method for identifying promising and generalizable inter- ventions for health systems delivery (Mills, 2008). For example, health systems research has led to some influential practices, such as integrating the manage - ment of childhood illnesses (Arifeen et al., 2004; Armstrong Schellenberg et al., 2004) or rethinking the desirability of user fees (a nominal fee charged for health services) (Holla and Kremer, 2009) or charging for bed nets or other health goods (Ashraf et al., 2007; Hoffmann et al., 2009). The Poverty Action Lab (PAL) at MIT tested the widely held belief that unless people pay for a productâin this case, for a bed netâthey will neither value nor use it. One PAL study in Kenya tested this theory and found no evi - dence that paying for a bed net will increase its use (Cohen and Dupas, 2009; Dupas, 2009). Interestingly, another study in Uganda showed that if you charge for a bed net, it is more likely to be used by the highest-income earner; but if you give it away for free, it is more likely to be used by mothers and small children, who are most vulnerable to malaria (Hoffmann, 2007, 2008). Health systems research is critically important for addressing pressing con - cerns such as human resource constraints and can offer approaches for delivering care in more efficient and creative ways (Bjorkman and Svensson, 2007). For example, in studies in India, giving a kilogram of lentils every time a child was immunized (and a set of plates with each additional dose) both increased immu - nization rates by 3 percent and reduced the cost per immunization. By placing a nurseâa limited resource and the greatest administrative expenseâin one location with bags of lentils, people were willing to walk up to 6 miles to get the lentils (and their child immunized) (Banerjee et al., 2008). Operational or implementation research tends to be more context-specific and focuses on promoting âthe uptake and successful implementation of evi - dence-based interventions and polices that have . . . been identified through systematic reviewsâ (Sanders and Haines, 2006). Increased support for opera - tional and implementation research would help to resolve many of the context-
THE U.S. COMMITMENT TO GLOBAL HEALTH specific barriers to deploying existing interventions more routinely (Madon et al., 2007). For example, strategies and drugs to prevent mother-to-child transmission of HIV, such as oral nevirapine prophylaxis, exist.1 Yet while the prevention of this mode of HIV transmission has proved highly efficacious in tightly controlled clinical trial settings, its effectiveness in real-world settingsâand thus its use - fulnessâis significantly diminished. Few women in low- and middle-income countries can access the required drug because the health systems in these coun - tries lack the necessary componentsâhuman resources, physical infrastructure, laboratory capacity, procurement and supply systems, and fiscal managementâto provide universal access to the drug (WHO, 2006). Operational research is urgently required for the uptake of this drug since vertical transmission of HIV/ AIDS from parents to children continues to infect more than 400,000 children with the disease each year (UNICEF, 2008). Similarly, other simple interventions with proven benefits, such as the provision of potable water, polio vaccines, and bed nets, also await operational research that can allow their benefits to be widely available. Operational and implementation research that includes cost-benefit analysis and acceptability studies will also be crucial before the scale-up of new interven - tions, such as the human papilloma virus vaccine to prevent infection and ensuing cervical cancer or male circumcision to reduce the likelihood of HIV infection. Policy makers in low- and middle-income countries will need to decide whether and how to add these interventions to their health programs, based on an array of factors including their cost-effectiveness and acceptability, but also larger issues such as disease burden and strain on the health system (Brooks et al., 2009; Saxenian, 2007). The committee finds that too often, research efforts fail to address break - downs in public health infrastructure and health systems delivery, such as poor surveillance systems, bottlenecks in drug supply pipelines, and chronic deficits in the health workforce. While additional research focused on cultural- and context- specific settings could allow the deployment of new interventions, it could also improve the deployment of several interventions already in use. The U.S. research community should support areas of study using operational, policy, and systems research to identify the desirable characteristics of interventions from the per- spective of end users and to influence policy making, thus enabling innovations to be disseminated and used globally. 1 A 1999 landmark randomized trial in Uganda testing the safety and efficacy of a single dose of oral nevirapine prophylaxisâgiven to mothers at the onset of labor and to infants within 72 hours of birthâshowed a 50 percent reduction (compared to zidvudine) in perinatal HIV transmission in breast-fed infants, who were followed up to age 14-16 weeks (Guay et al., 1999). Subsequent studies following these babies up to age 18 months demonstrated the drugâs continued efficacy, with a 41 percent reduction in vertical transmission of HIV seropositivity (Jackson et al., 2003).
GENERATE AND SHARE KNOWLEDGE Measure Impact of Programmatic Investments in Health Not only has research on healthcare systems been underutilized generally, but few programs that deliver specific health interventions undergo rigorous evaluation. This is a significant missed opportunity to understand how to improve programmatic efforts, for example, to understand why some households do not use newly installed water purification systems in spite of life-threatening disease or why children continue to fall ill to water-borne disease even after this service is provided. An assessment that only tracked the number of households that used water purification systems would not reveal that misuse of the water in the home perpetuated high rates of diseases. The importance of knowing what works is critical if U.S. health efforts are to help countries achieve sustainable and far-reaching outcomes. Evaluation should thus form an essential component of U.S. global health programs. Yet with the exception of the Millennium Challenge Corporation, a U.S. government corpora - tion established in 2004 to reduce global poverty through the promotion of sus - tainable economic growth, there has been little emphasis on evaluating impacts. Recent trendsâincluding the reorganization of foreign assistance under the State Department and the implementation of the Presidentâs Emergency Plan for AIDS Relief (PEPFAR)âhave focused significant attention on creating indicators for recording and monitoring purposes, such as the number of health workers trained or the number of pregnant women receiving HIV testing and counseling (PEP - FAR, 2007). Although such data on inputs (such as dollars spent) and outputs (such as vaccines delivered) are necessary for timely managerial decisions and accountability for the use of resources, they do not provide any useful informa - tion on the effect of U.S. interventions on saving lives and improving health. As a result, the United States has lost the opportunity to learn what kinds of programs are most effective and should be disseminated to other settings and which ones are yielding fewer benefits than they could. For example, an Institute of Medicine (IOM) evaluation of PEPFAR found that some of the indicators col - lected did not provide appropriate information on the progress being made toward the ultimate goal of controlling the AIDS epidemic. In its early stages, most of the results reported were for targets that could be measured only in the short term and therefore revealed more about the process of implementation than the impact of the program (IOM, 2007). In response, the PEPFAR reauthorization calls for impact evaluation to examine the effect of PEPFAR programs on indicators such as incidence, prevalence, and mortality. In addition to asking for measurement of inputs and outputs, Congress and other donors should require that program efforts be accompanied by rigorous country- and program-level evaluations to measure the effect of global health investments. Independent and rigorous evaluation, accompanied by careful study of the implementation process, is the recommended means of addressing policy questions of enduring importance. Beyond counting the number of vaccines
THE U.S. COMMITMENT TO GLOBAL HEALTH administered or health workers trained, it is important to ask tough questions such as, Are we preventing HIV infections in adolescent women? Do our efforts lead to sustained reductions in child mortality? Critical questions like these should inform future U.S. investments by improving knowledge of what does or does not work. For example, such questions could help the authorizers of PEPFAR go beyond simply knowing the sheer number of individuals who undergo HIV counseling to understand whether or not the program is actually lowering the rate of HIV infection within a target population. In order to arrive at this level of information, along with program-level evaluation, investments are needed for the expansion of country-based, reli- able, transparent, and long-term systems for recording health information. These should include complete (as far as possible) registration of births and deaths, along with details on the causes of death, and focused surveillance systems for infectious diseases. Indeed, such systems form the backbone of any rapid global response to new diseases and pandemics, such as severe acute respiratory syn - drome (SARS) and influenza, and will be needed to track sustained health gains in preventing infections such as HIV. Improved country-level tracking would also greatly enhance the success of partnerships with the Centers for Disease Control and Prevention, which has played a historically important role in surveillance (Levine, 2008b). Recommendation 3-1. The U.S. research community should increase research and evaluation efforts to address the systemic bottlenecks in health systems in low- and middle-income countries that keep the full benefits of existing medical and public health knowledge and technologies from being completely realized. (A) The U.S. research community should expand its research efforts through increased attention to health systems research (both for studies that can be generalized across countries and for operational and imple - mentation studies that are culturally and contextually relevant). (B) In addition to measuring inputs (such as dollars spent) and out- puts (such as drugs delivered), Congress and other global health funders should require that efforts to deliver health interventions be accompanied by rigorous country- and program-level evaluations to measure the effect of global health programs on saving lives and improving health. Continue Research to Develop Novel Health Technologies and Interventions Global health would greatly benefit from the development and dissemina - tion of a variety of novel behavioral and biomedical prevention strategies to combat infectious diseases. Antiquated diagnostics and treatments also need to be
GENERATE AND SHARE KNOWLEDGE improved to achieve sustainable results in the management and control of disease and to reduce drug resistance that results from misdiagnosis or poor adherence to treatment regimens (Dowdy et al., 2008). These steps are especially important given that new vaccines against the three major infectious diseases seem unlikely to be deployed for another decade or more. The research process involved in discovering, developing, and deploying a new biomedical technology is termed the âinnovation cycleâ by the World Health Organization (WHO) Commission on Intellectual Property Rights, Innovation and Public Health. It spans activities from basic science to translational studies; involves experts from multiple disciplines within and beyond the health and life sciences, such as behavioral scientists, chemists, engineers, and economists; and is conducted in partnership between local and global researchers, with the par- ticipation of the endemic communities. Its goal is to deliver good-quality inter- ventions that are effective, culturally appropriate, accessibly priced, and made available in sufficient quantities (see Box 3-2) (CIPIH, 2006). While the innova - tion cycle runs quite smoothly in high-income countries, it often breaks down in low- and middle-income countries due to gaps and inefficiencies at each stage (discovery, development, and delivery). The U.S. research community should both conduct and fund research to help fill these gaps and should create norms for sharing that make it easier to access the information and tools necessary for research in low- and middle-income countries. Continue Support of Product Development Partnerships to Deliver New Technologies One of the most promising approaches to bridge the enormous and widening gap in the availability of drugs, vaccines, and diagnostics to deal with the global disease burden is the creation of public-private product development partnerships. Tapping innovative philanthropic and government financing, PDPs combine cut - ting-edge technology with traditional product development to create new business models that address some of the worldâs most devastating scourges (Matlin et al., 2008; McKerrow, 2005). PDPs have brought together participants from the pub - lic and private sectors, maximizing their skills and resources to tackle complex issues of drug, vaccine, and diagnostic development and distribution (Meredith and Ziemba, 2008). In many instances, PDPs are virtual pharmaceutical and biotechnology companies, made operational by the commitment to achieve an important aim that would not be possible for any one partner acting alone: the development of products for which there is little potential financial return on investment. Although PDPs came into being only in the last 10 years, the global health field has already benefited enormously from their growth. One study found that the PDP approach, compared to when the commercial or public sectors act alone, was the most cost-efficient and delivered the best health outcomes for low- and
THE U.S. COMMITMENT TO GLOBAL HEALTH BOX 3-2 Identifying Promising Interventions The WHO Commission on Intellectual Property Rights, Innovation and Public Health identified an analytical framework laying out the four interrelated compo- nents that together define âthe right to health interventions and technologies.â According to this framework, interventions should be available, acceptable, a ccessible, and of quality, as detailed below. Available in sufficient quantities. To be available, the right kinds of interven- tions must exist. If they do not, the principal challenge is to spur innovation to c reate a product that fills the need. Where a suitable intervention already exists but is unavailable in adequate supply, solutions should be sought through research, such as the creation of a synthetic version of artemisinin, the antimalarial drug, because the natural product is in limited supply. Alternatively, an existing interven- tion may be suboptimal, such as current tuberculosis treatments that require six months of use and are cumbersome to administer. Then, too, an intervention may require effective procurement of existing products, the financing or subsidizing of production and distribution, or establishing effective delivery infrastructures. Acceptable, in terms of both their usability and their appropriateness, given cultural and other factors. This requires the right kinds of products, t ailored to the specific technical and social needs of the group that will use them. Knowledge is a critical element of creating acceptable interventions, such as knowledge of existing gaps in scientific know-how and clinical outcomes and of behavioral and cultural norms. This sort of knowledge requires its own kind of research and usually relies on epidemiological or social anthropological studies to understand the scale of the impact of a disease on a community or of the means required to achieve uptake of an intervention. Education and health systems r esearch can play an important role. The lowest possible cost to facilitate access. This requires the financing of research, and the availability of finance often drives the direction of research (HIV/ AIDS, for example, has greatly benefited from the active involvement of public sector institutions); affordable pricing of medicines; the financing of procurement that can help to scale up and manufacture new products; and access to existing products. Effective and of good quality. This requires standards for testing new p roducts, as well as incentives to conduct clinical trials in key populations. Par- ticular ethical and technical challenges need to be resolved for the testing of products on pregnant women and very young children, particularly those who are poor, marginalized, and often most at risk. SOURCE: Adapted from the Commission on Intellectual Property Rights, Innovation and Public Health, 2006.
GENERATE AND SHARE KNOWLEDGE middle-income country patients. PDP drug development trajectories matched or exceeded industry standards and were significantly faster than government drug development (Moran, 2005). The unique strengths of PDPsâtheir ability to gal - vanize sectors and research networks to identify the strongest selection of drug, vaccine, and diagnostic candidates; negotiate intellectual property, licensing, and pricing agreements early in the discovery process to ensure access and afford - ability for effective interventions; and react nimbly to opportunities within the research communityâhave laid the groundwork and provided lessons for future research endeavors across sectors and countries. The committee finds that continued investment in PDPs is essential. Several PDPs are now moving promising products into large-scale clinical trials; addi - tional and diverse funding will be needed to see these products through to devel - opment and to determine the best ways to deliver successful interventions. The U.S. government and private foundations should continue to support PDPs and other innovative research models that best address the unmet health needs of poor countries. The U.S. research community should continue to explore cross-sectoral collaboration to focus a diverse set of expertise on the discovery, development, and delivery of the new generation of cutting-edge biomedical advances that have the potential to revolutionize global health. Study the Basic Mechanisms of Diseases That Disproportionately Affect the Global Poor Most of the research being conducted on global health by the U.S. research community is biomedical research directed to just three diseases: AIDS, malaria, and tuberculosis (TB). This research is itself heavily biased toward vaccine and drug development and largely neglects diagnostic and platform technologies (technologies on which other technologies or processes are built) (Moran et al., 2009). However it is critical to develop and leverage both cutting-edge research tools and platform technologies because they facilitate innovation and attract the interest of leading research teams seeking breakthrough interventions, especially against the most neglected tropical diseases that have received little investment but place a high burden on low- and middle-income countries. These technical research tools are immensely valuable at every step of the discovery process, for example, in developing suitable animal models, identifying biomarkers, and validating surrogate end points for treatment. Platform technolo- gies such as proteomics, microarray, and high-throughput screening increase the efficiency of product development and allow researchers to make early decisions on whether or not to proceed with a promising lead. This is especially important given the high cost of biomedical research and the finite resources available for global health.
0 THE U.S. COMMITMENT TO GLOBAL HEALTH High-throughput screeningâa search for chemicals that act on a particular moleculeâis an example of a technology that enables drug developers to quickly test thousands of different compounds using robotic handling systems and auto - mated analysis of results. Such screening, along with computer-based screening using molecular docking,2 is commonly used by industry and, more recently, by the academic community. Increasingly, these techniques are also being applied to neglected diseases, with compound libraries in the public and private sectors being queried for drugs against conditions such as African sleeping sickness, leishmaniasis, Chagas disease, and schistosomiasis (McKerrow, 2005; Renslo and McKerrow, 2006). In one such example, the Sandler Center for Basic Research in Parasitic Diseases at the University of California, San Francisco (UCSF), established a consortium of core laboratories to develop new drugs for global parasitic dis - eases that have been ignored by the pharmaceutical industry. Initial work at the center focused on a drug lead for Chagas disease, which kills more people in Latin America than even malaria. A promising drug compound for Chagas was discovered by the UCSF team, with support from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH), and developed further by the Drugs for Neglected Diseases Institute (DNDi), a PDP, and the Institute for OneWorld Health, a nonprofit pharmaceutical company. Several other new technologies also hold the promise to unlock the secrets of biological questions and dramatically impact the way we prevent, diagnose, and treat illness on a global scale. Virus chip technology, a tool using DNA sequences to quickly identify disease agents (Wang et al., 2002), played a critical role in identifying SARS in 2002 (Frankish, 2003). Nutrigenomicsâthe study of gene- nutrient interactionsâindicates that âdietary imbalanceâ can increase the risk for noncommunicable diseases (Kaput and Rodriguez, 2004), showing the way to public health applications such as the response to chronic disease through dietary interventions. Genomicsâthe study of gene sequencing in living organismsâis expected to yield new preventive and therapeutic approaches to the treatment of global health diseases and to promote enduring food security in low- and middle- income countries. Genomics has already yielded an antimalarial drug that went into clinical trial in less than two years (Pang, 2002). In addition to the work being done to identify new drug targets, state-of-the- art technologies such as reverse vaccinology are revolutionizing the vaccine field (Bambini and Rappuoli, 2009; Serruto et al., 2009). Researchers are now using reverse vaccinology to help identify a serotype-independent vaccine to address pneumococcal disease. The compelling need for this vaccine has prompted sev - eral governments and other donors to fund an âAdvance Market Commitmentâ to further draw the commercial industry and nonprofit research institutes into apply- 2 Moleculardocking is a collective term that refers to theoretical methods and computational tech - niques to model or mimic the behavior of molecules.
GENERATE AND SHARE KNOWLEDGE ing the latest technological advances to develop a vaccine that would be condu - cive to fighting the disease in low- and middle-income countries (see Box 3-3). The application of cutting-edge science to the search for promising prod - ucts to address neglected poor-country diseases is now occurring in labs at universities and research institutes across the United States. The committee finds that increased support for basic research, with heightened attention to using cutting-edge research tools and platform technologies, is possible, timely, and indispensable. Investments in basic research, particularly for diseases and condi - tions that disproportionately affect poor populations, will generate the knowl - edge upon which lifesaving medical interventions can be developed. Universities BOX 3-3 An Advance Market Commitment (AMC) for Pneumococcal Vaccine Pneumococcal disease can cause severe infections and pneumonia; it kills close to 1 million children under 5 years of age worldwide every year (mostly in low- and middle-income countries) (CDC, 2007; WHO, 2007). These deaths tell only part of the story; an additional 11 to 20 million children are also hospitalized each year for pneumonia (Rudan et al., 2004). The pneumococcal vaccine rou- tinely administered in the United States covers 65 to 80 percent of the serotypes associated with invasive pneumococcal disease among young children in Western industrialized countries. Serotypes vary by region, however, and this coverage is lower in many low- and middle-income countries (WHO, 2007). Because existing vaccines for pneumococcal disease are too expensive and not the right serotypes for low- and middle-income countries, they are rarely administered. Why isnât there a serotype-independent pneumococcal vaccine? Addressing this question could go a long way toward helping to avoid the more than 10 million child deaths each year. The Pneumococcal Advance Market Commitment is an innovative finance mechanism that aims to stimulate faster progress in developing vaccines for pneumococcal diseases. Simply, an AMC guarantees innovators that there will be a market for their product if they commit the research and development neces- sary to produce it. In the pilot AMC program for pneumococcal vaccines, donors (including the Bill & Melinda Gates Foundation and Canada, Italy, Norway, Russia, and the United Kingdom) have committed $1.5 million to speed the development and availability of an effective vaccine. When such a vaccine becomes available, GAVI (Global Alliance for Vaccines and Immunization) and donor funds will help recipient countries purchase it at high prices for a guaranteed period of time. GAVI slowly phases out its co-financing, and when donor funds are depleted, recipient countries are responsible for buying the vaccine at a lower price without outside assistance. The design of the AMC assures vaccine developers that there will be an initial market at high prices for their product, under the agreement that after donor funding runs out, the vaccine will be available at lower, affordable prices (AMC, 2007).
THE U.S. COMMITMENT TO GLOBAL HEALTH and research institutes undertaking such research should be strongly supported through grants from philanthropies and the U.S. government. Adapt Existing Knowledge for Low- and Middle-Income Countries While many areas require further research to identify novel technologies to address the health conditions of the global poor, additional attention is also required to adapt existing tools and interventions to better serve the global poor. Even when interventions for disease already exist, deploying them more widely and effectively in low- and middle-income countries and in distinct sociocultural settings can be very difficult, hampering global health progress (GFHR, 2004). Increasing utilization can often be achieved through adaptations to technologies and interventionsâfor example, by developing vaccines that do not require cold storage or modifying a behavior change program to adapt to the local context. Relatively minor adaptations can improve the effectiveness of certain interven- tions, such as combining drug regimes to improve clinical performance and combat drug resistance. An example of such a modification can be seen in the treatment of malaria. At a time when malaria mortality and morbidity were on the rise due to wide - spread resistance to antimalarial drugs, a new combination of artesunate with another antimalarial drug was seen to confer significant clinical benefit (White et al., 1999). While such artemisinin-based combination therapies, or ACTs, are currently the most effective medicines for malaria, they are typically much more expensive than traditional malaria treatments (Garner, 2004; WHO, 2001a). In response, a variety of public-private initiatives have arisen to lower the barriers to producing ACTs and making them widely available. WHO entered into a special pricing agreement with Novartis (the manufacturer of the first ACT to be prequalified by WHO) to provide drugs at cost to governments in malaria- endemic countries; a pediatric, cherry-flavored tablet that dissolves in water or breast milk and tastes like fruit juice has now been devised to improve the drugâs acceptability (Novartis, 2009). Another combination therapy using two off-patent and thus cheap drugs, artesunate and mefloquine, was formulated under DNDiâs Fixed-dose Artesunate-based Combination Therapies project in collabo - ration with Brazilâs Farmanguinhos/Fiocruz to treat patients in Latin America and Southeast Asia (DNDi, 2008). To further ensure the widespread availability of ACTs, the Affordable Medicines Facility for Malaria was initiated in 2009. This partnershipâoriginally suggested in the 2004 IOM report Saving Lives, Buying Timeâaims to negotiate lower prices and provide copayments for ACTs to expand access to successful malaria treatment and reduce the drug resistance that can occur with less effective treatments (IOM, 2004). Adapting vaccines to suit low- and middle-income countries would be another way to increase the use of an existing intervention. According to WHO, vaccine-preventable diseases such as measles, hepatitis B, and Haemophilus
93 GENERATE AND SHARE KNOWLEDGE influenzae type b (Hib) disease cause an estimated 2.7 million deaths each year. However, vaccine delivery in low- and middle-income countries is hindered by the need to provide refrigerated transport and storage, multiple doses over the course of months or years, and the use of injections, which are unacceptable in some cultures. Improvements in vaccine delivery were identified as one of the Gates Grand Challenges (Grand Challenges in Global Health, 2008); scientists are exploring various alternatives to needle-based delivery of vaccines that are not dependent on refrigeration and that can be delivered in conjunction with other major vaccines (Juma and Yee-Cheong, 2005). The need to adapt existing technologies for use in low- and middle-income countries goes well beyond the arena of infectious diseases and biomedical tools. Noncommunicable diseases such as heart disease and cancer have increased dramatically in low- and middle-income countries, but the pace at which proven therapies and preventive measures for these diseases are adapted and deployed there is not commensurate with the extent and public health impact of this epide- miological transition. Several lifesaving medicines are now available generically and can be produced cheaply, providing an opportunity to save lives in low- and middle-income countries. Evidence suggests that a âpolypillâ combining three blood pressure lowering drugs at low doses with a statin, aspirin, and folic acid could reduce cardiovascular events by more than 80 percent in healthy individuals (TIPS, 2009). The patients studied were middle-aged (45-80 years) Indian men and women without previ - ous cardiac disease, but with at least one cardiovascular risk factor: high blood pressure, obesity, high cholesterol, diabetes, or smoking (Cannon, 2009). This polypill strategy may provide important insights into adapting and delivering existing therapies to tackle growing chronic diseases in settings where access to physicians and healthcare providers is sporadic or difficult (Cannon, 2009). The idea of prescribing a single pill without lifestyle changes (such as smoking ces - sation) to prevent cardiovascular diseases, however, is controversial. Opponents argue that it could it could lead to excessive medication and mask the major causes of cardiovascular mortality, such as those related to lifestyle or socioeco - nomic status (Costantino et al., 2007). Behavioral interventions to combat noncommunicable diseases also need to be adapted to low- and middle-income-country settings, since several of the most prominent noncommunicable diseasesâlung cancer, hypertension, and diabe - tesâcan be mitigated by behavioral change. For example, smoking prevention and cessation programs have been tested extensively in high-income countries as strategies against lung cancer. The implications and extrapolation of these results to low- and middle-income countries are less understood and require appropriate behavioral trials in local settings (Buekens et al., 2004). The committee finds the need to devote immediate attention to our contin- ued inability to bring existing and future promising health interventions to the most disadvantaged populations. The U.S. research community has not yet fully
THE U.S. COMMITMENT TO GLOBAL HEALTH capitalized on opportunities to adapt existing technologies and interventions to low- and middle-income countries. Recommendation 3-2. The U.S. research community, in collaboration with global partners, should leverage its scientific and technical capabilities to conduct research using state-of-the-art technology and innovative strategies to address health problems endemic to low- and middle-income countries. (A) The U.S. research community should continue to examine new inter- ventions for the prevention and treatment of global infectious diseases. (B) The U.S. research community should expand its research efforts in global health with heightened attention to two purposes: (1) to study the basic mechanisms of diseases that disproportionately affect the global poor, and (2) to identify means to control communicable and noncom - municable diseases by adapting existing knowledge for low- and middle- income countries. SHARE KNOWLEDGE THAT ENABLES LOCAL PROBLEM SOLVERS3 Research on global health involves not only generating knowledge relevant to the context of low- and middle-income countries, but also effectively trans- ferring such knowledge and technologies to these settings and ensuring that the intended beneficiaries can apply them on a sustained basis. All of this requires the involvement of researchers on the ground in low- and middle-income countries. With research increasingly conducted globally through virtual communities of geographically dispersed scientists, it is critically important that information be made available to in-country researchers through a global network to exchange ideas and scientific tools, promote sustainable cross-country research partner- ships, and enable the timely dissemination of best practices for local problem solvers. Opportunities for more productive collaboration have been made possible by novel technologies, especially those in the biological and medical sciences, with dramatic benefits in how medical research is conducted; how new information is published, stored, retrieved, and used; how scientists and clinicians communicate with each other; how diseases are monitored and tracked; and how medicine is practiced. However, these developments also present their own set of challenges. Several factors affect the sharing of knowledge, such as the nature of the knowl - edge and the norms for scientific exchange. For example, even as information 3 Inpreparing this section of the report, the committee drew heavily on the background paper prepared by Dr. Anthony So and Mr. Evan Stewart (see Appendix F).
GENERATE AND SHARE KNOWLEDGE technology has changed the speed and marginal cost of disseminating knowledge, intellectual property rights can make such knowledge costly to acquire. Even in the absence of patents, a technology that is new to low- and middle-income countriesâsuch as conjugation technology for vaccine productionâmay not easily transfer without technical assistance. Norms related to the ownership of knowledge also influence the sharing of knowledge. These norms are rooted in statutes and regulations such as the Bayh-Dole Act, prevailing practices among research institutions and competing scientists, and guidance provided by funding agencies (So and Stewart, 2009). Access to the Building Blocks for Research In the path from bench to bedside (laboratory discoveries to medical treat - ments), the research continuum consists of inputs and outputs, each of which depends on the sharing of knowledge. Three stages in this continuum warrant closer scrutiny because decisions at these points significantly affect what knowl - edge can later be shared within the scientific community (So and Stewart, 2009). The three important elements relating to these stages are (1) access to scientific publications, (2) the norms for data and material sharing, and (3) patenting and licensing practices. Characterizing the obstacles to and opportunities for each can help point the way to paths that lower the barriers to sharing knowledge and improve the scientific communityâs ability to respond to health challenges. Access to Scientific Publications One of the challenges to sharing knowledge through scientific publications is that the subscription price of journals is often unaffordable for researchers in low- and middle-income countries. Mailing hard copies of journals to these countries is also prohibitively expensive for research institutes in the advanced economies. Several strategies have been deployed to ensure greater access to such publica- tions, such as tiered pricing or the pooling of published research in open access journals or repositories. With the advent of the Internet, much of this access can now be offered electronically, provided that health workers and researchers are equipped with computers and high-speed access to the Internet (see Box 3-4). The WHO-led Health InterNetwork Access to Research Initiative (HINARI) is one example of a tiered-pricing approach for enabling online access to scien - tific publications. Launched in January 2002, HINARI seeks to provide tiered access to more than 6,200 major journals in biomedicine and related social sci - ences. In collaboration with participating publishers, HINARI divides low- and middle-income countries into two groups: (1) countries with a gross national income (GNI) per capita from $1,250 to $3,500 per year, whose institutions can receive access for $1,000 per year, and (2) countries below this GNI level whose institutions receive free access. HINARI has claimed that between 2002 and
THE U.S. COMMITMENT TO GLOBAL HEALTH BOX 3-4 Improving Connectivity in Low- and Middle-Income Countries In an ideal world, everyone in the field of global health would have access to the digital tools needed to benefit from global research advances. In reality, of course, low- and middle-income countries lag far behind the advanced economies in access, despite some improvements, such as the use of the Internet and mobile technologies. For example, only 4 percent of the sub-Saharan African popula- tion uses the Internet, as opposed to 74 percent in North America (World Bank, 2007). Continued commitments are clearly needed for long-term investments in infrastructure to bring more people around the world âonline.â A unique opportu- nity now exists for the U.S. government and other donors to invest in information technology and infrastructure that would encourage more efficient communication among the multiple players in the global health arena. The following actions are required to facilitate such connectivity: â¢ ndustries, governments, and universities that control routes of communi- I cation over the Internet through cables or satellites should develop proce- dures for sharing these routes with global health programs and activities that have inadequate resources, especially in countries with weak digital infrastructure. â¢ unders of global health programs and activities should ascertain the digi- F tal support available to personnel and repair any deficiencies that impede communication or performance. â¢ esearch teams, global health practitioners, and meeting organizers should R support virtual collaboration and strive to take advantage of Internet-based convening opportunities, such as Webinars and interactive websites, to reduce the time and expense involved in traveling to meetings. â¢ he U.S. government and other funders of research should provide in- T centives for the adoption of available technologies that allow connectivity between the field and medical personnel for diagnosis, surveillance, and delivery of health care. They should also aggressively support the research and development of transformational technologies that would help close the digital divide by allowing data transfer to benefit public health. 2006, researchers in HINARI countries increased their rates of publication by 63 percent, while those in non-HINARI nations saw only a 38 percent increase (Nightingale, 2008). The pooling of published research in open access journals or repositories is an alternative method of increasing access in low- and middle-income countries. Open access journals provide articles online without charging subscriber fees because they raise their revenue from other sources, such as upfront author fees. Several studies show that this free online access corresponded to higher mean citation rates in disciplines ranging from electrical engineering to mathematics
GENERATE AND SHARE KNOWLEDGE (Antelman, 2004; Eysenbach, 2006; Hajjem et al., 2005; Lawrence, 2001). Nota - bly, the impact of public access publication on citations in journals was twice as strong in low- and middle-income countries (Evans and Reimer, 2009). Several health research funding agencies require investigators to make their publications accessible following publication. The NIH Public Access Policy requires investigators to submit final, peer-reviewed journal manuscripts arising from NIH funding to PubMed Central upon acceptance for publication. The Well- come Trust requires submission of scientific publications resulting from its grants into UK PubMed Central within six months of the publication date, and even provides funding for the upfront fees associated with publishing in truly open access journals that make content freely available immediately upon publication (Wellcome Trust, 2007). Investigators in the Howard Hughes Medical Institute also face a similar requirement to deposit publications in PubMed within six months of publication (Howard Hughes Medical Foundation, 2007). By retaining copyright and granting a nonexclusive license to journals, authors can also self-archive their work, oftentimes on their own websites or in a university repository. For example, in early 2008, the Faculty of Arts and Sciences at Harvard University adopted its own public access mandate whereby members submit electronic copies of all completed articles to an institutional repository that will eventually be accessible worldwide via the Internet (Guter- man, 2008). This practice has spread: Harvard Law School and Harvardâs Ken - nedy School of Government recently adopted their own public access initiatives, as have the Stanford University School of Education, Boston University, and the Massachusetts Institute of Technology (Gavel, 2009; Jahnke and Ullian, 2009; Suber, 2008; Taylor, 2009). Access to Research Data and Materials The sharing of data and other research materials enables the scientific com - munity to confirm study findings and also to build upon the work of others. Aggregating efforts thus lowers the transaction costs by sharing the building blocks of research. Unlike the electronic distribution of journal articles or data, the marginal cost of disseminating research materials may not be negligible, cre - ating barriers to sharing. Competing public policy concerns can also sometimes set limits on their sharing; for example, some data may risk the personal privacy of human subjects or compromise the confidentiality of privileged proprietary information (So and Stewart, 2009). Dual-use technologiesâdeveloped for mili - tary purposes but adapted for industrial or consumer usesâhave the potential both to advance scientific knowledge and to pose threats to public health or the environment; such research activities as well as resulting data and materials thus require government or institutional oversight (Davidson et al., 2007). At the same time, emerging infectious diseases have highlighted the need for a more rapid and free exchange of information and materials. During the 2003
THE U.S. COMMITMENT TO GLOBAL HEALTH SARS outbreak, WHOâs Global Influenza Surveillance Network played a key role in linking the worldâs leading laboratories and experts with real-time information (Heymann and Rodier, 2004). In the race to identify the coronavirus as the cause of SARS, 11 laboratories recruited by WHO regularly and voluntarily shared samples of the unknown virus and held conference calls to discuss their results (Surowiecki, 2004). Without this level of collaboration and sharing, the transmis - sion of SARS might not have been halted within four months. In times of public health crises, data sharing is crucial but can also lead to conflict over the ownership of information. To study the avian flu virus, research - ers in high-income economies are dependent upon low- and middle-income countries to supply them with wild virus samples. However the patenting of avian flu wild virus samples sent to laboratories in the advanced economies and the likely high costs of any resulting vaccines recently created friction in the Global Influenza Surveillance Network. The refusal of Indonesia to share virus samples with WHO Collaborating Centers without an assurance of sharing in later benefits highlighted the importance of a bidirectional flow of benefits in the sharing of data and materials (Khor and Shashikant, 2008). Advances in mobile phone and Internet technologies have an increasingly vital role in disease surveillance. Text (or SMS) messages can be used as an alert system for the public, and personal data assistant phones can help physicians improve critical response times (Park et al., 2008). Today, more than half of the disease outbreaks investigated by WHO have come to its attention from informal sources such as news media, press reports, chat rooms, and blogs (Heymann and Rodier, 2001). Automated systems such as HealthMap (see Figure 3-1) seek to expedite health surveillance strategies by integrating web-based information around the globe into one tracking system that reports disease outbreaks in real time (Freifeld, 2009). FIGURE 3-1 All diseases reported to HealthMap from January 14 to February 12, 2009. 3-1.eps SOURCE: Freifeld, 2009.
GENERATE AND SHARE KNOWLEDGE Despite the significant challenges to creating repositories and sharing the knowledge from them, some promising developments can be seen in different but complementary approaches to broadening access to compound libraries used to find new treatments for neglected diseases. Tackling a range of neglected diseases, the Special Programme for Research and Training in Tropical Diseases (TDR) has launched a web portal, TDR Targets, to bring together data and anno - tation in a publicly accessible database on tropical disease pathogens. Users can undertake searches ranging from genomic or protein structural data to target drug ability on neglected diseases, or they can find information on diseases such as leprosy, filariasis, and Chagas disease. In the first 16 months since the launch of the database, the site has logged more than 10,000 visits, with more than 30 percent coming from low- and middle-income countries or regions where these neglected diseases are endemic (AgÃ¼ero et al., 2008). This web-based initiative complements other efforts to bring together the partnerships and multidisciplinary networks needed for drug discovery for neglected diseases (Senior, 2007). Funding agencies have again played an important role in setting norms for sharing data and materials. The U.S. Department of Health and Human Services has developed a clinical trial registry (ClinicalTrials.gov) and data bank for the results of both federal and privately supported clinical trials conducted around the world. The Food and Drug Administration (FDA) Amendments of 2007 strengthened reporting requirements by requiring that clinical trial results com - pleted before product approval be submitted to ClinicalTrials.gov no later than 30 days after the drug or device has received FDA approval (United States Code, 2007). Building upon the momentum of these efforts, WHO has sought to provide a forum for developing best practices for clinical trial registration, and a number of countries now maintain prospective trial registries (WHO, 2009b). Access to Patented Inventions The patenting and licensing of inventions significantly influences the sharing of knowledge. The patenting of knowledge enhances its potential commercial value by rewarding the inventor with time-limited market exclusivity and can help mobilize needed private sector resources for further research and develop - ment. The approach to licensing the patent shapes the conditions of access and the sharing of knowledge (So and Stewart, 2009). Tiering can be applied to patents and their licensing in the same way it applies to scientific publications, data, and material transfers. By setting limits of geography or use, licenses may offer royalty-free rates for the inventionâs application in low- and middle-income countries. For example, in 2002, the TB Alliance signed an agreement with Chiron Corporation (now part of Novartis) for an anti-TB compound, PA-824. Chiron owned all the patents, know-how, and data for PA-824, as well as hundreds of its chemical analogues. The license agree- ment granted the TB Alliance exclusive worldwide rights for the development of
00 THE U.S. COMMITMENT TO GLOBAL HEALTH TB drugs, and in an unprecedented move for a pharmaceutical or biotechnology company, Chiron agreed to take no royalty payments in low- and middle-income countries. Such licenses often promise little revenue return from these countries, but by reserving rights for application in the advanced economies, revenues from paying markets remain possible. The role of academic licensing in global access visibly surfaced in 2001 at Yale University in the case of the AIDS drug Zerit. The compound d4t had been discovered by two Yale researchers with funding from NIH and Bristol Myers Squibb (BMS) in the early 1990s. In exchange for the funding, as is common practice in most U.S. academic institutions, BMS was granted an option to claim broad patent protection for the compound, which it subsequently exercised. In 2001, however, Doctors Without Borders requested a waiver of the South African patent. BMS rejected this request, leading to student protests on the Yale campus and increased public attention to the critical importance of the drug to thousands in South Africa. BMS then agreed not to assert its rights. This led to an awakening on university campuses across the United States. Several universities have since taken measures to ensure that their research is accessible to researchers in low- and middle-income countries. For example, Boston University has made the decision to ask its faculty not to assert intellec - tual property rights on their patents when the intervention is used by global public health organizations, such as WHO or the United Nations Childrenâs Fund, to enable access in publicly funded programs in low- and middle-income countries (Stevens, 2009). Funders have also sought to mitigate the concerns over exclusive licensing of inventions by establishing patent policies and requiring access provisions. Various foundations have issued guidance that encourages greater sharing of inventions resulting from their research, sometimes incorporating such condi - tions into their grant agreements. In funding point-of-care diagnostics for moni - toring AIDS, the Doris Duke Charitable Foundation assessed how preexisting intellectual property affected the ability of its grantees to make good on the charitable objective of ensuring the technologyâs availability at an affordable cost in low- and middle-income countries. The grant agreements also allowed the foundation to retain a nonexclusive, royalty-free license to any patents filed in these countries, giving it the ability to sublicense rights to make and distribute the product if the grantee failed to deliver on the charitable objective (Doris Duke Charitable Foundation, 2004). Pooling patents can also help lower the transaction costs associated with assembling the tools needed to conduct research on a health technology. GlaxoSmithKline recently developed a patent pool, or an agreement among organization to share patents, through which it contributed more than 80 current and pending patent families (GlaxoSmithKline, 2009). This voluntary patent pool makes available the patented knowledge it uses to develop medicines for neglected diseases to other drugs companies, governments, and nongovernmental
0 GENERATE AND SHARE KNOWLEDGE organizations. In order to enhance access to any drugs that are developed through the patent pool in low-income countries, GlaxoSmithKline has promised to cap the prices of these drugs at less than 25 percent of their potential price in high- income nations. Recommendation 3-3. The U.S. research community should promote global knowledge networks and the open exchange of information and tools that enable local problem solvers to conduct research to improve the health of their own populations. (A) Funders of global health research should require that all work sup- ported by them will appear in public digital libraries, preferably at the time of publication and without constraints of copyright (through open access publishing), but no later than six months after publication in traditional subscription-based journals. Universities and other research institutions should foster compliance with such policies from funding agencies and supplement those policies with institution-based repositories of publica - tions and databases. (B) The U.S. government, universities, and other research institutions should develop new methodsâsuch as simplified web-based procedures for executing agreements such as materials transfer and nondisclosure agreementsâto expedite the sharing of information and research materi - als with researchers in low- and middle-income countries. (C) Scientists, clinicians, advocates, and other personnel involved in defined areas of global health should develop trustworthy websites that aggregate published literature, incorporate unpublished databases or clini- cal trial information, promote digital collaboration, and disseminate news and other information about common interests. (D) Universities and other research institutions that receive federal and philanthropic funding to conduct research should adopt patent policies and licensing practices that enable and encourage the development of technologies to create products for which traditional market forces are not sufficient, such as medicines, diagnostics, and therapeutics that primarily affect populations in low- and middle-income countries. REFERENCES AgÃ¼ero, F., B. Al-Lazikani, M. Aslett, M. Berriman, F. S. Buckner, R. K. Campbell, S. Carmona, I. M. Carruthers, A. W. E. Chan, F. Chen, G. J. Crowther, M. A. Doyle, C. Hertz-Fowler, A. L. Hopkins, G. McAllister, S. Nwaka, J. P. Overington, A. Pain, G. V. Paolini, U. Pieper, S. A. Ralph, A. Riechers, D. S. Roos, A. Sali, D. Shanmugam, T. Suzuki, W. C. Van Voorhis, and C. L. M. J. Verlinde. 2008. Genomic-scale prioritization of drug targets: The TDR targets database. Nature Reviews Drug Discovery 7(11):900-907.
0 THE U.S. COMMITMENT TO GLOBAL HEALTH Alliance for Health Policy and Systems Research. 2004. Strengthening health systems: The role and promise of policy and systems research. Geneva, Switzerland: Global Forum for Health Research. AMC (Advance Market Commitment). 2007. What is an AMC? http://www.vaccineamc.org/about. html (accessed June 18, 2009). Antelman, K. 2004. Do open access articles have a greater research impact? College & Research Libraries News 65(5):372-382. Arifeen, S. E., L. S. Blum, D. M. Emdadul Hoque, E. K. Chowdhury, R. Khan, P. R. E. Black, P. C. G. Victora, and J. Bryce. 2004. Integrated management of childhood illness (IMCI) in Bangladesh: Early findings from a cluster-randomised study. Lancet 364(9445):1595-1602. Armstrong Schellenberg, J. R. M., T. Adam, H. Mshinda, H. Masanja, G. Kabadi, O. Mukasa, T. John, S. Charles, R. Nathan, K. Wilczynska, L. Mgalula, C. Mbuya, R. Mswia, F. Manzi, D. De Savi - gny, D. Schellenberg, and P. C. Victora. 2004. Effectiveness and cost of facility-based integrated management of childhood illness (IMCI) in Tanzania. Lancet 364(9445):1583-1594. Ashraf, N., J. Berry, and J. M. Shapiro. 2007. Can higher prices stimulate product use? Evidence from a field experiment in Zambia. Working paper . Cambridge, MA: National Bureau of Economic Research. Bambini, S., and R. Rappuoli. 2009. The use of genomics in microbial vaccine development. Drug Discovery Today 14(5-6):252-260. Banerjee, A., E. Duflo, R. Glennerster, and D. Kothari. 2008. Improving immunization coverage in rural India: A clustered randomized controlled evaluation of immunization campaigns with and without incentives. Cambridge: Massachusetts Institute of Technology. Bjorkman, M., and J. Svensson. 2007. Power to the people: Evidence from a randomized field experi- ment of a community-based monitoring project in Uganda. Policy research working paper . Washington, DC: World Bank. Brooks, R. A., M. Etzel, L. E. Klosinski, A. A. Leibowitz, S. Sawires, G. Szekeres, M. Weston, and T. J. Coates. 2009. Male circumcision and HIV prevention: Looking to the future. AIDS and Behavior:1-4. Bryce, J., S. El Arifeen, G. Pariyo, C. F. Lanata, D. Gwatkin, and J. P. Habicht. 2003. Reducing child mortality: Can public health deliver? Lancet 362(9378):159-164. Buekens, P., G. Keusch, J. Belizan, and Z. A. Bhutta. 2004. Evidence-based global health. Journal of the American Medical Association 291(21):2639-2641. Cannon, C. P. 2009. Can the polypill save the world from heart disease? Lancet 373(9672):1313- 1314. CDC (Centers for Disease Control and Prevention). 2007. Global pneumococcal disease and vaccine. http://www.cdc.gov/vaccines/vpd-vac/pneumo/global.htm (accessed April 14, 2009). CIPIH (Commission on Intellectual Property Rights, Innovation and Public Health). 2006. Public health, innovation and intellectual property rights: Report of the Commission on Intellectual Property Rights, Innovation and Public Health. Geneva, Switzerland: WHO. Cohen, J., and P. Dupas. 2009. Free distribution or cost-sharing? Evidence from a randomized ma- laria prevention experiment. Cambridge, MA: Poverty Action Lab. Costantino, G., E. Ceriani, A. M. Rusconi, and N. Montano. 2007. Prevention of cardiovascular disease with a polypill. Lancet 369(9557):185-186. Davidson, E. M., R. Frothingham, and R. Cook-Deegan. 2007. Practical experiences in dual-use review. Science 316(5830):1432-1433. DNDi (Drugs for Neglected Diseases Initiative). 2008. ASMQ: Innovative partnership delivers new treatment. http://www.actwithasmq.org/ (accessed May 17, 2009). Doris Duke Charitable Foundation. 2004. Medical research program bulletin. http://www.ddcf.org/ doris_duke_files/download_files/MRPBulletinOct04.pdf (accessed May 5, 2009). Dowdy, D. W., R. E. Chaisson, G. Maartens, E. L. Corbett, and S. E. Dorman. 2008. Impact of enhanced tuberculosis diagnosis in South Africa: A mathematical model of expanded cul- ture and drug susceptibility testing. Proceedings of the National Academy of Sciences USA 105(32):11293-11298.
0 GENERATE AND SHARE KNOWLEDGE Dupas, P. 2009. What matters (and what does not) in householdsâ decision to invest in malaria preven - tion? American Economic Review: Papers & Proceedings 99(2):224-230. Evans, J. A., and J. Reimer. 2009. Open access and global participation in science. Science 323(5917): 1025. Eysenbach, G. 2006. Citation advantage of open access articles. PLoS Biology 4(5):692-698. Fenner, F., D. A. Henderson, I. Arita, Z. JeÅ¾ek, and I. D. Ladnyi. 1988. Smallpox and its eradication. Geneva, Switzerland: WHO. Foege, W. H. 1998. Commentary: Smallpox eradication in West and Central Africa revisited. Bulletin of the World Health Organization 76(3):233-235. Foege, W. H., J. D. Millar, and D. A. Henderson. 1975. Smallpox eradication in West and Central Africa. Bulletin of the World Health Organization 52(2):209-222. Frankish, H. 2003. SARS genome chip available to scientists: The NIAID hopes that widespread access to the SARS genome chip will catalyse research into effective treatments for the virus. Lancet 361(9376):2212. Freifeld, C. 2009. The HealthMap project. Presentation to IOM Committee on the U.S. Commitment to Global Health, Washington, DC: Childrenâs Hospital Boston, Harvard Medical School, MIT Media Laboratory. Garner, P. 2004. Artesunate combinations for treatment of malaria: Meta-analysis. Lancet 363(9402): 9-17. Gavel, D. 2009. Harvard Kennedy School faculty votes for open access for scholarly articles. http://www.hks.harvard.edu/news-events/news/press-releases/open-access-vote (accessed May 5, 2009). GFHR (Global Forum for Health Research). 2004. Monitoring financial flows for health research. Geneva, Switzerland: GFHR. GlaxoSmithKline. 2009. An intellectual property pool for neglected tropical diseases in least devel- oped countries. http://www.gsk.com/research/patent-pool.htm (accessed May 17, 2009). Grand Challenges in Global Health. 2008. Goal : Improve vaccines. http://www.grandchallenges. org/ImproveVaccines/Pages/default.aspx (accessed May 5, 2009). Guay, L. A., P. Musoke, T. Fleming, D. Bagenda, M. Allen, C. Nakabiito, J. Sherman, P. Bakaki, C. Ducar, M. Deseyve, L. Emel, M. Mirochnick, M. G. Fowler, L. Mofenson, P. Miotti, K. Dransfield, D. Bray, F. Mmiro, and J. B. Jackson. 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354(9181):795-802. Guterman, L. 2008. Harvard faculty adopts open-access requirement. Chronicle of Higher Educa- tion News Blog. http://chronicle.com/news/article/3943/harvard-faculty-adopts-open-access- requirement (accessed May 5, 2009). Hajjem, C., S. Harnad, and Y. Gingras. 2005. Ten-year cross-disciplinary comparison of the growth of open access and how it increases research citation impact. IEEE Data Engineering Bulletin 28(4). Henderson, D. A. 1999. Eradication: Lessons from the past. Morbidity and Mortality Weekly Report 48(SU01):16-22. Heymann, D. L., and G. Rodier. 2001. Hot spots in a wired world: WHO surveillance of emerging and re-emerging infectious diseases. Lancet Infectious Diseases 1(5):345-353. âââ. 2004. Global surveillance, national surveillance, and SARS. Emerging Infectious Diseases 10(2):173-175. Hoffmann, V. 2007. Mental accounts, gender, or both? The intrahousehold allocation of free and purchased mosquito nets. Washington, DC: Center for Global Development. âââ. 2008. Psychology, gender, and the intrahousehold allocation of free and purchased mosquito nets. Washington, DC: Center for Global Development. Hoffmann, V., C. B. Barrett, and D. R. Just. 2009. Do free goods stick to poor households? Experi - mental evidence on insecticide treated bednets. World Development 37(3):607-617. Holla, A., and M. Kremer. 2009. Pricing and access: Lessons from randomized evaluations in educa- tion and health. Washington, DC: Center for Global Development.
0 THE U.S. COMMITMENT TO GLOBAL HEALTH Howard Hughes Medical Foundation. 2007. Public access to publications. http://www.hhmi.org/ about/research/sc320.pdf (accessed May 5, 2009). IOM (Institute of Medicine). 2004. Saving lives, buying time: Economics of malaria drugs in an age of resistance. Washington, DC: The National Academies Press. âââ. 2007. PEPFAR implementation: Progress and promise. Edited by C. C. Jaime SepÃºlveda, James Curran, William Holzemer, Helen Smits, Kimberly Scott, and Michele Orza. Washington, DC: The National Academies Press. Jackson, J. B., P. Musoke, T. Fleming, L. A. Guay, D. Bagenda, M. Allen, C. Nakabiito, J. Sherman, P. Bakaki, M. Owor, C. Ducar, M. Deseyve, A. Mwatha, L. Emel, C. Duefield, M. Mirochnick, M. G. Fowler, L. Mofenson, P. Miotti, M. Gigliotti, D. Bray, and F. Mmiro. 2003. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to- child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 362(9387):859-868. Jahnke, A., and J. Ullian. 2009. University Council approves open access plan. BU Today. http://www. bu.edu/today/node/8320 (accessed May 5, 2009). Juma, C., and L. Yee-Cheong. 2005. Reinventing global health: The role of science, technology, and innovation. Lancet 365(9464):1105-1107. Kaput, J., and R. L. Rodriguez. 2004. Nutritional genomics: The next frontier in the postgenomic era. Physiol Genomics 16(2):166-177. Khor, M., and S. Shashikant. 2008. Developing countries look to WHA for solution to flu virus is - sue. Third World Network. http://www.twnside.org.sg/title2/avian.flu/news.stories/afns.005.htm (accessed May 5, 2009). Lawrence, S. 2001. Free online availability substantially increases a paperâs impact . Nature 411(6837):521. Leroy, J. L., J. P. Habicht, G. Pelto, and S. M. Bertozzi. 2007. Current priorities in health research funding and lack of impact on the number of child deaths per year. American Journal of Public Health 97(2):219-223. Levine, R. 2008a. Case studies in global health: Millions saved. Sudbury, MA: Jones and Bartlett Publishers. âââ. 2008b. Healthy foreign policy: Bringing coherence to the global health agenda. In The White House and the world: A global development agenda for the next U.S. President, edited by N. Birdsall. Washington, DC: Center for Global Development. Madon, T., K. J. Hofman, L. Kupfer, and R. I. Glass. 2007. Implementation science. Science 318(5857): 1728-1729. Matlin, S., A. d. Francisco, L. Sundaram, H.-S. Faich, and M. Gehner, eds. 2008. Health partnerships review. Geneva, Switzerland: GFHR. McKerrow, J. H. 2005. Designing drugs for parasitic diseases of the developing world. PLoS Medicine 2(8):e210. Meredith, S., and E. Ziemba. 2008. The new landscape of product development partnerships (PDPs). In Health partnerships review, edited by S. Matlin, A. d. Francisco, L. Sundaram, H.-S. Faich, and M. Gehner. Geneva, Switzerland: GFHR. Mills, A. 2007. Strengthening health systems. In The Commonwealth health ministers book 00. London, UK: Commonwealth Secretariat and Henley Media Group. âââ. 2008. The role of research in strengthening health systems. Presentation to IOM Committee on the U.S. Commitment to Global Health, Washington, DC: London School of Hygiene and Tropical Medicine. Moran, M. 2005. A breakthrough in R&D for neglected diseases: New ways to get the drugs we need. PLoS Medicine 2(9):e302. Moran, M., J. Guzman, A.-L. Ropars, A. McDonald, T. Sturm, N. Jameson, L. Wu, S. Ryan, and B. Omune. 2009. Neglected disease research and development: How much are we really spending? Sydney, Australia: The George Institute for International Health.
0 GENERATE AND SHARE KNOWLEDGE Morel, C. M., T. Acharya, D. Broun, A. Dangi, C. Elias, N. K. Ganguly, C. A. Gardner, R. K. Gupta, J. Haycock, A. D. Heher, P. J. Hotez, H. E. Kettler, G. T. Keusch, A. F. Krattiger, F. T. Kreutz, S. Lall, K. Lee, R. Mahoney, A. Martinez-Palomo, R. A. Mashelkar, S. A. Matlin, M. Mzimba, J. Oehler, R. G. Ridley, P. Senanayake, P. Singer, and M. Yun. 2005. Health innovation networks to help developing countries address neglected diseases. Science 309(5733):401-404. Nightingale, K. 2008. Subsidised access âhelps boost scientific output.â SciDevNet. http://www.scidev. net/en/news/subsidised-access-helps-boost-scientific-output-.html (accessed May 5, 2009). Novartis. 2009. Rolling back malaria. http://www.corporatecitizenship.novartis.com/patients/access- medicines/access-in-practice/malaria.shtml (accessed July 2, 2009). Pang, T. 2002. The impact of genomics on global health. American Journal of Public Health 92(7): 1077-1079. Park, H. I., W. K. Min, W. Lee, H. Park, C. J. Park, H. S. Chi, and S. Chun. 2008. Evaluating the short message service alerting system for critical value notification via PDA telephones. Annals of Clinical and Laboratory Science 38(2):149-156. Patouillard, E., C. A. Goodman, K. G. Hanson, and A. J. Mills. 2007. Can working with the private for-profit sector improve utilization of quality health services by the poor? A systematic review of the literature. International Journal for Equity in Health 6. PEPFAR (Presidentâs Emergency Plan for AIDS Relief). 2007. The Presidentâs Emergency Plan for AIDS Relief: Indicators, reporting requirements, and guidelines. Washington, DC: PEPFAR. Renslo, A. R., and J. H. McKerrow. 2006. Drug discovery and development for neglected parasitic diseases. Nature Chemical Biology 2(12):701-710. Research!America. 2006. 00 U.S. Investment in global health research. Alexandria, VA: Research! America. Rudan, I., L. Tomaskovic, C. Boschi-Pinto, and H. Campbell. 2004. Global estimate of the incidence of clinical pneumonia among children under five years of age. Bulletin of the World Health Organization 82(12):895-903. Sanders, D., and A. Haines. 2006. Implementation research is needed to achieve international health goals. PLoS Medicine 3(6):e186. Saxenian, H. 2007. HPV vaccine adoption in developing countries: Cost and financing issues. New York: International AIDS Vaccine Initiative/Program for Appropriate Technology in Health. Senior, K. 2007. Web initiative for neglected diseases. Lancet Infectious Diseases 7(6):377-377. Serruto, D., L. Serino, V. Masignani, and M. Pizza. 2009. Genome-based approaches to develop vac - cines against bacterial pathogens. Vaccine 27(25-26):3245-3250. So, A., and E. Stewart. 2009. Sharing knowledge for global health. Durham, NC: Duke University. Stevens, A. 2009. Sharing information, knowledge and materials. Presentation to IOM Committee on the U.S. Commitment to Global Health, Washington, DC: Institute for Technology Entrepre - neurship and Commercialization, School of Management, Boston University. Suber, P. 2008. OA mandate from the European research council. Open Access News. http://www. earlham.edu/~peters/fos/2008/01/oa-mandate-from-european-research.html (accessed May 5, 2009). Surowiecki, J. 2004. The wisdom of crowds: Why the many are smarter than the few and how collec- tive wisdom shapes business, economies, societies, and nations. New York: Doubleday. Taylor, M. 2009. MIT moves toward open access. Wall Street Journal. http://blogs.wsj.com/digits/ 2009/03/25/mit-moves-toward-open-access/ (accessed May 5, 2009). TIPS (The Indian Polycap Study). 2009. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): A phase II, double-blind, randomised trial. Lancet 373(9672):1341-1351. Tucker, J. B. 2001. Scourge: The once and future threat of smallpox. New York: Grove Press. UNESCO (United Nations Educational, Scientific, and Cultural Organization). 2005. UNESCO sci- ence report 00. Paris, France: UNESCO.
0 THE U.S. COMMITMENT TO GLOBAL HEALTH UNICEF (United Nations Childrenâs Fund). 2008. Children and HIV and AIDSâproviding paediatric treatment. http://www.unicef.org/aids/index_preventionMTCT.html (accessed May 11, 2009). United States Code. 2007. Title VIII-clinical trial databases. Sec. 801. Expanded clinical trial registry data bank. Public law 110-85. Walley, J., M. A. Khan, S. K. Shah, S. Witter, and X. Wei. 2007. How to get research into practice: First get practice into research. Bulletin of the World Health Organization 85(6):424. Wang, D., L. Coscoy, M. Zylberberg, P. C. Avila, H. A. Boushey, D. Ganem, and J. L. DeRisi. 2002. Microarray-based detection and genotyping of viral pathogens. Proceedings of the National Academy of Sciences USA 99(24):15687-15692. Wellcome Trust. 2007. Wellcome Trust position statement in support of open and unrestricted access to published research. http://www.wellcome.ac.uk/doc_WTD002766.html (accessed May 5, 2009). White, N. J., F. Nosten, S. Looareesuwan, W. M. Watkins, K. Marsh, R. W. Snow, G. Kokwaro, J. Ouma, T. T. Hien, M. E. Molyneux, T. E. Taylor, C. I. Newbold, T. K. Ruebush Ii, M. Danis, B. M. Greenwood, R. M. Anderson, and P. Olliaro. 1999. Averting a malaria disaster. Lancet 353(9168):1965-1967. WHO (World Health Organization). 2001a. Antimalarial drug combination therapy: Report of a WHO technical consultation. Geneva, Switzerland: Roll Back Malaria/WHO. âââ. 2001b. Macroeconomics and health: Investing in health for economic development. Report of the Commission on Macroeconomics and Health. Geneva, Switzerland: WHO. âââ. 2006. HIV treatment access reaches over million in sub-Saharan Africa, WHO reports. http:// www.who.int/mediacentre/news/releases/2006/pr38/en/index.html (accessed July 8, 2008). âââ. 2007. Pneumococcal conjugate vaccine for childhood immunizationâWHO position paper. Weekly Epidemiological Record 82(12):93-104. âââ. 2009a. Smallpox. http://www.who.int/mediacentre/factsheets/smallpox/en/ (accessed March 19, 2009). âââ. 2009b. The WHO registry network. http://www.who.int/ictrp/network/en/index.html (ac- cessed May 1, 2009). WIPO (World Intellectual Property Organization). 2008. World patent report: A statistical review. Geneva, Switzerland: WIPO. World Bank. 2007. Quick query, selected from World Development Indicators. http://ddp-ext. worldbank.org/ext/DDPQQ/member.do?method=getMembers&userid=1&queryId=135 (ac- cessed July 2, 2009).