Global Health Interventions and Artificial Intelligence

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Home >Nursing homework help >Global Health Interventions and Artificial Intelligence

Courtesy of Mark Tuschman.

Skolnik, Richard. Global Health 101, Jones & Bartlett Learning, LLC, 2019. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/indianatech-ebooks/detail.action?docID=5894023. Created from indianatech-ebooks on 2022-10-05 02:42:17.

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CHAPTER 18 Science, Technology, and Global Health

LEARNING OBJECTIVES

By the end of this chapter, the reader will be able to do the following:

■ Articulate the needs for diagnostics, vaccines, and drugs to address high-burden diseases that affect the poor in low- and middle-income countries

■ Assess the extent to which existing products meet those needs

■ Note the potential of science and technology to develop new products to address high-burden diseases

■ State some of the key constraints to investments in such products

■ Indicate mechanisms to overcome these constraints and encourage the development and uptake of new diagnostics, vaccines, and drugs

■ Outline lessons for future efforts from selected cases of new product development

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J ▶ Vignettes

uan lived in the highlands of Peru. He had tuberculosis (TB) and was being treated at a local TB clinic. He had to take four

drugs for the first 2 months of his treatment and two drugs for 4 months after that. Juan felt better within weeks of starting his drugs but struggled to take the remaining pills because there were so many to take and he had to take them for so long.

Wezi lived in South Africa, where about 19 percent of the adults are HIV-positive. Despite intensifying efforts to reduce the spread of new HIV infections in South Africa, the number of these infections is still large. In fact, the latest estimates suggest there were about 270,000 new infections in 2017 and that about 7.2 million people in South Africa are now living with HIV/AIDS. Some people believe that stopping the transmission of HIV in countries like South Africa will depend on the discovery of a safe, effective, and affordable HIV vaccine.

Mei-Ling was 4 years old and lived in the west of China. Like so many children in her region, Mei-Ling was infected with hookworms. The community had a deworming program, and every 6 months Mei-Ling was given medicine to get rid of the worms. This medicine was generally safe and effective. However, it had to be given twice a year, and there was some indication that the hookworms were becoming resistant to it.

David was 7 years old and lived in the eastern part of Kenya. He had a high fever and chills, and his mother took him to the local health clinic. The nurse there examined David, decided he had malaria, and prescribed antimalarial medicine. This was the third time in a year that David had malaria. A safe, effective, and affordable malaria vaccine would have prevented him from getting

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malaria, being sick so often, missing so much school, and spending so much money on medical care.

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▶ Introduction Scientific and technological progress has contributed substantially to improvements in human health. Such progress has included, for example, new and more effective diagnostics for a range of diseases; vaccines for a number of potential killers; a variety of drugs, such as penicillin; and safer and more effective family planning devices.

In fact, some scientific and technological discoveries have been of exceptional importance to public health. The discovery of the smallpox vaccine led to the first important efforts at vaccination and ultimately to the eradication of smallpox. Jonas Salk’s discovery of the polio vaccine began to eliminate the scourge of polio from many societies, and his work was advanced further by Albert Sabin’s work on the oral polio vaccine. It is difficult to imagine living in a world without antibiotics but they emerged only just before World War II.

The enhancement of medical devices has also had an important impact on public health. The invention of the bifurcated needle was instrumental in enhancing the effectiveness of the smallpox eradication campaign. The intraocular lens for cataracts has provided a very low-cost tool for improving visual acuity.

The purpose of this chapter is to examine how science and technology could assist in speeding up the development and dissemination of new products that could address the largest burdens of disease in low- and middle-income countries. First, the chapter examines the characteristics that such products need to possess if they are to have the desired impact. Next, the chapter reviews the extent to which some existing diagnostics, vaccines, and drugs have those traits. The chapter then discusses the potential of science and technology to develop products in

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selected areas of importance and reviews constraints to product development. Several case studies illustrate the key concepts of the chapter.

As you read this chapter, it is very important that you keep several things in mind. First, you should remember that very substantial gains in health could be obtained from the effective implementation of existing technologies. There are a number of low-cost but highly effective interventions that are well known but not used widely enough:

■ Reducing maternal disability and deaths through better identification of complications, speedy transport to the hospital, and appropriate emergency obstetric care

■ Reducing neonatal deaths by training birth attendants in resuscitation, keeping the baby warm, and providing antibiotics for infection

■ Reducing young child deaths by expanding vaccination coverage with the six basic antigens and Hib, rotavirus, and pneumococcal vaccines

■ Reducing infant morbidity and mortality by promoting exclusive breastfeeding for 6 months

■ Reducing morbidity and mortality from TB by expanding case finding and cure rates

■ Better controlling hypertension to reduce the risk of stroke

In addition, we must remember that better hygiene practices, such as handwashing with soap, do not require the development of any new products but could substantially improve health.

As you read this chapter, it is also important to keep in mind that the development of new products will not be a quick fix. Rather, while supporting the continued search for scientific and technical progress, it is critical to continue to focus on the underlying sources of ill health in low- and middle-income countries. These

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include, among other things, poverty, the lack of education, the lack of political interest in the health of the poor, and the place of some minority groups and women in society. Enhancing basic infrastructure, water, and sanitation will also be critical in many settings to sustainable improvements in health.

Finally, you should note that this chapter focuses on a narrow range of the scientific and technological matters that concern global health. It looks largely at new product development, the constraints to it, and what might be done to speed up the process. It does not examine research or operational research. Nor does it focus on the dissemination of existing technologies.

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▶ The Need for New Products As we think about the characteristics of diagnostics, drugs, vaccines, and medical devices that could most effectively and efficiently address the critical health problems of low- and middle- income countries, we need to keep several points in mind. First, the most important target groups for these products are poor people. Their financial resources are limited, and the countries in which they live, particularly low-income countries, generally spend little per capita on health. Second, the quality of care in many countries is low and injection safety is often poor. Third, many low- and middle-income countries have health systems that are poorly organized and cannot effectively manage logistics. In addition, transport and storage of goods is weak, and the supply of electricity for keeping goods cool is often limited.

In this light, what are some of the ideal characteristics of diagnostics, drugs, vaccines, and medical delivery devices to help address the most critical burdens of disease in low- and middle- income countries? The most important of these characteristics are shown in TABLE 18-1.

TABLE 18-1 Some Ideal Characteristics of Diagnostics, Vaccines, Drugs, and Delivery Devices

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As you can see in the table, it is important that diagnostics be specific, sensitive, easy to use, and noninvasive. Ideally, diagnostic tests could be done quickly by relatively untrained workers and would rapidly produce easy-to-read results. They would also be easy to transport, heat stable, inexpensive, and not require refrigeration.

Much the same would be true for the ideal drugs. These drugs would be safe, effective, inexpensive, and have a long shelf life. They could also be used for many years without becoming susceptible to resistance. In addition, the number of pills that patients would have to take would be limited, and patients would not have to take them for very long.

Vaccines to meet the most important health needs in low- and middle-income countries would also be safe, effective, and inexpensive. They would be easy to transport and store, would be heat stable, and would not require refrigeration. The ideal vaccines would be an inexpensive combination of many antigens, and only one dose would confer lifelong immunity against a number of diseases. It would also be ideal if therapeutic vaccines, which are vaccines that can be used to treat diseases rather than prevent them, could be developed for some diseases.

The present state of key products does not meet the ideals noted here. Until recently, for example, a child receiving full coverage of the six basic antigens in many countries would require six contacts with the health system to get all of these vaccines.

Could vaccines be developed that combine required antigens in such a way that only a few contacts would be needed between the health system and patients to fully vaccinate a child? The pentavalent vaccine is a step in this direction.

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There is a cultural preference in many societies for injections, despite problems with injection safety. Could vaccines be delivered in noninvasive ways, such as sprays, air injectors, and skin patches, that would be safe, effective, heat stable, easy to transport, not very costly, and culturally acceptable?

There is a vaccine for tuberculosis and drugs that are effective against TB. However, the effectiveness of the TB vaccine against adult pulmonary TB is variable. In addition, the drugs that are used to treat TB require a large pill burden, and TB bacteria are increasingly becoming resistant to some of them. What is needed to develop new drugs for TB that could make treatment shorter and easier? Is it possible to develop a safe TB vaccine that could be effective against all forms of TB?

Artemisinin-based combination therapy is effective against malaria that is resistant to chloroquine, although resistance to artemisinin is already growing. However, the cost per treatment with this drug, even at globally negotiated prices, has been about 10 times the cost per treatment with chloroquine for children and 20 times the cost for adults. The search for a malaria vaccine has gone on for many years, and there has been some progress in developing and testing a vaccine. However, there is only one vaccine, RTS,S, that has shown any efficacy in reducing the burden of malaria in young children, when combined with other interventions, and it is now being carefully piloted in a number of countries. What would it take to develop additional low-cost and highly effective malaria drugs? What can encourage the development of a safe and even more effective malaria vaccine?

Drugs for HIV/AIDS can control the virus for most people but cannot cure them. In addition, many people develop resistance to those drugs, and some of the drugs have important side effects. Moreover, there is still no preventive or therapeutic vaccine for HIV/AIDS. How can the world encourage the development of safer

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and more effective HIV/AIDS drugs, an HIV/AIDS vaccine, and mechanisms, such as microbicides, by which women could protect themselves better from the risk of HIV?

The scientific and technological gaps indicated previously also apply to some of the neglected diseases. Despite the ubiquity of hookworm, there is no vaccine for this parasite, the drug used to treat it has to be administered regularly, and resistance to it is increasing. Can a safe, effective, easy-to-use, affordable vaccine be developed for hookworm and some of the other “wormy” diseases?

PHOTO 18-1 There has been a large gap between the burden of disease in low-income countries and the focus of medical research. However, more and more scientists and researchers from low-income countries are being trained. How might one spur scientific collaboration between higher- and lower-income countries to promote more research on the “unfinished agenda”

in nutrition, maternal and neonatal conditions, and communicable diseases?

Courtesy of Mark Tuschman.

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▶ The Potential of Science and Technology Scientific progress has led to a number of areas in which science could be harnessed to address some of the gaps noted in the previous section and to improve human health. Four such areas, as examples, are noted in this section.

Sequencing the genomes of important pathogens will help scientists better understand why they cause disease, how they develop resistance, and what drugs can best fight them, while reducing the onset of resistance. The genomes have been sequenced for more than 30,000 microbial species. The speed with which the SARS virus was sequenced is an indication of the speed with which this can be done, if sufficient priority is given to this work. The sequencing of the mosquito genome may allow scientists to engineer mosquitoes so that they cannot carry malaria and other diseases, such as lymphatic filariasis. Scientists have already sequenced the genome of 16 species of Anopheles mosquito, including the Anopheles stephensi mosquito, a key vector of malaria throughout the Indian subcontinent. This research has provided new insights into mosquito biology and mosquito–parasite interactions, which have important implications for the prevention of malaria transmission.

Improvements in information technology, chemistry, and robotics, as well as in genetic and molecular epidemiology, will also facilitate the development of new and better drugs. These tools will allow scientists to understand better the nature of disease. They will also enable scientists to more quickly try different chemical compounds to address those pathogens.

In addition, a number of technologies exist that can assist in the design and manufacture of new and improved vaccines. The use of recombinant DNA technology, for example, helped an Indian

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vaccine company reduce the cost of the hepatitis B vaccine from about $8 to 50 cents. DNA technology should also be very helpful to the development of drugs.

Genetic modification of plants is a controversial subject because, among other things, there are concerns over the environmental and health risks associated with it. Yet, it is possible to engineer plants that can carry higher levels of certain nutrients, such as vitamin A, while being very resistant to disease. In addition, plants can be modified genetically so that they can produce edible vaccines. However, while research on this front has provided proof of the concept, no such vaccine is very far along in development.

There is an increasing understanding of the promise of science and technology for improving global health. In one study, the views of 28 experts were sought about the biotechnologies that could help improve health in low- and middle-income countries in the following 5 to 10 years. In particular, these scientists were polled about how these potential biotechnologies could :

■ Improve health ■ Be affordable and appropriate in low- and middle-income

countries ■ Have an ability to address the most pressing health needs ■ Be developed in the next 5 to 10 years ■ Advance knowledge ■ Yield important indirect benefits

They were also asked how they would use science and technology to achieve these aims. As the highest priority, these scientists would use biotechnology to develop new diagnostics, vaccines, and drugs, in that order. They would use technology to improve the environment, including water and sanitation. The scientists also put a premium on the development of products that can help

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empower women to protect themselves against sexually transmitted diseases, including HIV, such as microbicides.

In fact, the Grand Challenges initiative aims to engage the world’s most innovative researchers in defining and addressing critical research and operational challenges in global health. The Bill & Melinda Gates Foundation launched the initiative in 2003, in conjunction with the Canadian Institute for Health Research, the Foundation for the U.S. National Institutes of Health, and the Wellcome Trust. This effort has now grown into a family of initiatives, supported largely by the Gates Foundation, Canada, and USAID. To date, these programs have awarded 2,390 grants in 90 countries. The list of members of the Grand Challenges initiative is shown in TABLE 18-2.

TABLE 18-2 The Grand Challenges Initiatives

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Grand Challenges began by focusing on scientific innovation to increase access to diagnostics, drugs, and vaccines that could help address the needs of poor people in low- and middle-income countries. TABLE 18-3 indicates some of the specific areas of involvement supported earlier by Grand Challenges. Today, this family of initiatives supports innovation in a number of fields, including the diagnosis and control of a range of diseases, reproductive health, nutrition, agricultural development, child welfare, and education. TABLE 18-4 indicates the thematic areas of some recent Grand Challenges grants that are related to global health.

TABLE 18-3 Selected Goals of Grand Challenges in Global Health

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TABLE 18-4 Thematic Areas of Selected Recent Grand Challenges Grants for Global Health

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▶ Constraints to Applying Science and Technology to Global Health Problems

Given the strengths of existing scientific knowledge, why is it that some of the products that could make an important difference to the health of the poor globally have not been developed? Beyond the inherent scientific difficulties in some of these efforts, such as the development of HIV and malaria vaccines, there are several common constraints to the development of these desired products. First, much of the research and development on new diagnostics, vaccines, drugs, and delivery devices is carried out in the for-profit sector, and that sector has historically believed it could not make a sufficient return from products oriented toward low- and middle- income countries. These firms see the market for their goods in low- and middle-income countries as a small one. They also doubt the ability of governments and individuals in low-income countries to pay prices for their products that would give them a sufficient return on their capital. As evidence of this, for example, they pointed earlier to the slow uptake in low- and middle-income countries of the vaccines against Haemophilus influenzae type b (Hib) and hepatitis B.

Moreover, the costs of research and development on new products can be very high, some suggesting as high as $800 million, to bring a new drug from research to market. Given these costs, profit-making firms will invariably want to use their capital to develop, for example, a potential blockbuster drug against high cholesterol that can be sold in high-income countries, rather than a drug for low-income countries on which the firm believes it will not be able to recoup its investment.

In addition, vaccine markets have some particular constraints to entry. Vaccine development requires a considerable amount of

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upstream investment, the cost of developing vaccine candidates is very high, and governmental regulations may also reduce the potential for sufficient profit from vaccines to attract firms to this market. In addition, the number of firms engaged in vaccine production worldwide is small and production capacity is limited. The development of vaccines for low- and middle-income country markets has also been complicated by the fact that, until recently, vaccine manufacturers often had to produce formulations of vaccines for some low- and middle-income countries that were different from the relatively expensive combination vaccines that were used in other countries. Moreover, pharmaceutical companies can generally earn a higher return on money invested in the development of drugs than money invested in developing vaccines.

Another constraint to greater focus on the health conditions of low- and middle-income countries until recently has been insufficient attention to them by some of the major national research institutions. The basic research that is conducted at places like the U.S. National Institutes of Health often sets a foundation for product development later by the for-profit manufacturers. The greater the attention that national research institutes in high- income countries pay to the high-burden problems of low- and middle-income countries, the greater the likelihood that new products for them will eventually be developed.

Some of these constraints are reflected in the extent to which drugs have been developed to address diseases that most affect poor people in low- and middle-income countries. A study of drugs that were approved for marketing showed that between 1975 and 1999, for example, 1,393 new chemicals were approved, but only about 3 percent were relevant to infectious and parasitic diseases that are the most significant burdens of disease in low-income countries. The same study looked at the number of new drugs

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approved for every million DALYs and found that two to three times more drugs were produced for every million DALYs attributable to diseases of high-income countries, rather than diseases of low- and middle-income countries. Over the same period, only about 1 percent of the drugs approved concerned neglected tropical diseases, and only about 0.2 percent concerned TB. Moreover, about 90 percent of expenditure on research and development on health has been oriented toward the diseases of the high-income countries, and only about 10 percent toward the diseases of the low- and middle-income countries. The Global Forum for Health Research called this the “10/90 gap.”

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▶ Enhancing New Product Development

We have seen that gaps in the development of diagnostics, drugs, vaccines, and medical devices that serve the needs of low- and middle-income countries reflect market failures. In general, the public sector tries to reduce its risks by waiting for such products to be developed by the private sector. However, the private sector generally believes that it is too risky to produce products that are expensive to develop and for which an adequate return on investment cannot be assured. Is it possible to change the market for these products? Can one reduce the cost of product research and development to the point where the private for-profit sector might be interested in such products? What other steps can be taken to speed product development?

Push Mechanisms A number of steps could encourage a larger share of research and development to focus on the needs of low- and middle-income countries. Some of these are shown in FIGURE 18-1, which depicts push and pull mechanisms and where in the product development cycle they have the most impact.

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FIGURE 18-1 Push/Pull Mechanism for Product Development

Modified from Glass, S. N., Batson, A., & Levine, R. (2008). Issues paper:

Accelerating new vaccines. Geneva, Switzerland: Global Alliance for Vaccines and

Immunizations.

One type of effort is called “push mechanisms.” These refer to mechanisms meant to encourage product development by reducing the risks and costs of investments. Push mechanisms could include the following :

■ Direct financing: government financing or carrying out of research activities needed to develop a product.

■ Performing or facilitating clinical trials: This could include government measures to make it easier to carry out clinical trials for the product and to help with the ethical issues involved in such trials.

■ Tax credits for research and development: Governments can lower the cost to firms of research and development by giving

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them credits against their taxes for certain investments.

These push mechanisms operate on the early stages of product development. Such mechanisms have been used successfully before. In addition, they can reduce risk and thereby encourage investment in product development. The disadvantage of push mechanisms, however, is that there is no guarantee that they will lead to the development of a desired product. In addition, even if a product is developed, it may not be the best one, and product developers will then not produce what might have been better candidates. Furthermore, when the money is spent on push mechanisms, it is gone, whether or not a product has been developed.

Some of the direct financing and facilitation of clinical trials could be done through programs like the U.S. National Institutes of Health or similar institutes in other countries. Additional money could also be channeled, for example, to the Special Program for Research and Training in Tropical Diseases (TDR), which is sponsored by the World Health Organization (WHO), UNICEF, the United Nations Development Programme, and the World Bank. Some of the financing of the Bill & Melinda Gates Foundation, like that for Grand Challenges, is meant to push new product development.

In conjunction with these efforts, it is important to strengthen the links between researchers in low- and middle-income countries and those in high-income counties. The links can also be enhanced among researchers in low- and middle-income countries. The aim of these efforts would be to attract more research money to institutions within the low- and middle-income countries that are engaged in research and development on the most important burdens of disease in such countries. A number of low- and middle-income countries, especially India, China, Brazil, South Africa, Mexico, Indonesia, and Cuba, already have the

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ability to carry out basic research and to develop products that emanate from that research. Additional funding might deepen and speed their research, as Grand Challenges intends to do.

It is also important to comment on some aspects of governmental regulation of pharmaceutical and vaccine development. Regulation is necessary, but it is also an important part of the costs of research and development. By arranging to speed drug approvals and harmonize approval processes across countries, the costs of research and development can be reduced to provide some incentives to manufacturers. Granting fast-track approval for generic AIDS drugs, for example, has encouraged the development of such drugs.

Pull Mechanisms A number of mechanisms are intended to help ensure that a future return is provided to those who do develop new products. These are called pull mechanisms. The following are some of the most important pull mechanisms :

■ Increasing the uptake of existing vaccines: Using public funds to increase the use of vaccines that have not been taken up sufficiently.

■ Prizes: Offering monetary rewards to those firms that develop desired products.

■ Transferable patents: In exchange for the development of the desired product, providing the manufacturer with the right to extend a patent on another one of its products or patents in markets in high-income countries.

■ Copayments: Governments can provide the manufacturer with a payment for every product sold.

■ Market assurances: The public sector can promise to buy the products if they are produced.

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■ Tax credits for vaccine sales: Governments can offer tax credits for products that are sold.

From the point of view of the public sector, pull mechanisms have the advantage of providing funds only when desired products have been developed. However, governments and the private sector have to agree early on what such arrangements would be for any product, and neither party might be satisfied with these arrangements when products do emerge. There has been little experience until recently with financing mechanisms that are meant to exert a pull on new product development and use, but the Advance Market Commitments and the International Finance Facility for Immunisation are now in place and are discussed later in the chapter.

A mechanism that has been used for vaccines for some time and more recently for AIDS drugs is called tiered pricing. This is an arrangement by which a firm charges different prices in different markets. The idea behind tiered pricing is that a firm can charge enough to make a profit in high-income markets to offset the fact that the products will not make a profit in low- and middle-income markets. The profits from one market could cross-subsidize the sales at reduced prices in other markets. This is being practiced now for some drugs for which there is a global market. However, tiered pricing is not likely to work effectively for products that are needed exclusively in low- and middle-income countries because the basis for cross-subsidizing will not exist.

In addition, considerable hope has been put until recently into the role that public–private partnerships can play in encouraging the development of the diagnostics, drugs, vaccines, and medical devices that could have a significant impact on the health of the poor in low- and middle-income countries. As indicated earlier, many of these efforts are organized around the search for new products for particular diseases, such as HIV, TB, and malaria.

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These public–private partnerships are also referred to as product development partnerships (PDPs) and are organized on a not-for- profit basis. They aim to attract private, public, and philanthropic funds to invest in needed research and development, tapping the strengths of the private sector in product development as they do so. There are now PDPs for a number of vaccines and drugs, including, for example, TB and malaria. The PDP arena, however, has changed recently with the establishment by the Gates Foundation of its own medical research institute.

Meeting product development goals will probably require a combination of these efforts. First, they can start with a greater focus by research institutions in high-income countries on the problems of low- and middle-income countries. They can also promote greater networking of research institutions in low- and middle-income countries. This can help encourage product development, with other push mechanisms. At the same time, it will be important to change the market and perceptions of the market for needed products through pull mechanisms that can ensure that money will be available for products if they are developed. Third, the public and private sectors can collaborate with each other, bringing complementary skills and financing to the partnership.

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▶ Case Studies This section contains a number of case studies that highlight some of the different approaches to harnessing science and technology to enhance new product development and improve health outcomes. Mobile technology and telemedicine are increasingly used in health work in many countries, and this section begins with a case study on each of those topics. This is followed by case studies that touch on the development of new diagnostics for TB and a device intended to reduce the risk of maternal hemorrhage. The next case study discusses cooperative efforts to develop a meningitis vaccine for Africa. The last cases concern innovative financing mechanisms that are intended to provide a pull on new product development and diffusion: the advance market commitments (AMC) and the International Finance Facility for Immunisation (IFFIm).

mHealth: Using Mobile Technology to Improve the Health of the Poor in Poor Countries What Is mHealth? mHealth, or mobile health, is commonly defined as medical and public health practice supported by mobile devices, such as mobile phones, patient monitoring devices, personal digital assistants (PDAs), and other wireless devices that can transmit text messages, photos, and data at the touch of a button. TABLE 18-5 lists the different categories of mobile health technologies, potential applications, and selected examples of mHealth programs. mHealth is a rapidly growing area in the development of health technology and is a component of eHealth, or the delivery of health care by electronic means. More than 90 percent of the world is now covered by a mobile network, and as a result, the

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overwhelming majority of WHO member countries have mHealth programs. The largest expansion of mHealth has occurred in the Asia-Pacific region due to more extensive mobile data networks. mHealth has seen the largest barriers in Africa, due largely to limited infrastructure, but great progress has been made there, as programs such as SIMpill and Child Count+ demonstrate. Within low- and middle-income countries, mHealth has been more commonly adopted in healthcare areas related to maternal and child health, HIV/AIDS, and primary care. There is hope that

mHealth can offer cost-effective programs and interventions to support the performance of health workers and disseminate health education information, especially in places where health systems face significant challenges of human and physical resources.

TABLE 18-5 WHO Classification of mHealth Technologies

Technology Category Applications Example Programs

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What Is the Scope of mHealth? In 2009, the World Health Organization conducted the second global survey of mHealth technologies and used a classification system based on six categories to describe the scope of mHealth initiatives globally.

Although there are many programs that fall within these categories, there is substantial innovation in mHealth, and there is greater diversity of mHealth than these categories capture. For example, applications have been developed that allow mHealth to help support the diagnostic process, while other applications act as attachments to traditional medical tools such as the stethoscope.

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Communication: Individuals to Health Services One of the most common mHealth initiatives has been the creation of health call centers that allow individuals to call in or text health questions and receive immediate answers. These help lines have been developed with the goal of increasing access to health advice and information, while overcoming potential barriers, such as shortage of healthcare professionals and the costs of service provision and transportation. For example, a medical hotline called Healthline in Bangladesh received more than 3.5 million calls in its first 3 years of operation from individuals seeking answers from a licensed health professional. Similarly, an initiative called the Ligne Verte (Green Line) toll-free hotline was introduced in the Democratic Republic of the Congo to provide confidential family planning information and to refer patients to nearby clinics that offer contraception services. Each call cost the equivalent of $0.36. The most successful of these healthcare centers in meeting their stated aims have been operated by for-profit organizations that partner with mobile network operators. As a result, health call centers may not be as accessible to the poor as desired.

Communication: Health Services to Individuals One of the greatest challenges in many health systems is patient compliance. A 2007 pilot study in South Africa demonstrated that when a mobile application technology, SIMpill, was introduced, patient compliance could jump to over 90 percent in areas previously recording 22 percent to 60 percent compliance. This application is a medication container that communicates with a patient’s mobile phone to remind the patient about the timing of the next medication dose. Repeated or missed dosages are brought to the attention of healthcare workers, who then follow up with the patient and arrange for an in-person visit.

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General Consultations Telemedicine initiatives have also been widespread and can help improve the quality of care for rural populations by creating more opportunities for interaction with qualified medical professionals in urban settings. Many pilot telemedicine programs have been successful, including a program in Taiwan that had an 85 percent accuracy rate in the remote diagnosis of soft tissue injuries. Other telemedicine programs have attempted to enhance the referral process by facilitating communication among physicians. The Mobile Doctors Network (MDNet) in Ghana was launched in 2008 and was the first program in Africa to provide free mobile-to-mobile voice and text services to all physicians in Ghana. It has been successful in enhancing physician connectivity, the frequency of consultations, the success rate of diagnosis and treatment for populations with limited access to specialized care, the time needed for referral, and the patient’s recovery experience. The start-up costs for telemedicine projects can be minimal if telecommunications providers are incentivized to donate the infrastructure and resources such as SIM cards, but the cost- effectiveness of these types of efforts is still being investigated.

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Emergency Communication In emergency situations, a rapid response can be the difference between life and death. Although emergency response systems in high-income countries are well established, those in low- and middle-income countries are often limited or nonexistent. Nonetheless, mHealth offers applications that at low cost can capitalize on the mobile network coverage that does exist in these low-resource settings. On a national scale, for example, nationwide alert systems can be implemented through these networks. After the 2010 Haitian earthquake, three mHealth organizations—Ushahidi, FrontlineSMS, and SamaSource— created a logistics map using short message service (SMS) alerts for missing people or immediate humanitarian needs that was widely used by aid organizations throughout Haiti. Unfortunately, these types of programs have only been evaluated in a limited manner.

Monitoring and Surveillance An array of mHealth technologies has been used for health monitoring and surveillance. Senegal piloted a program called Episurveyor that indicated that only 55 percent of the country’s health districts were systematically using partograms, graphical tools that monitor the trajectory of labor in a pregnant woman. Based on the information from this survey, Senegal’s Ministry of Health was able to increase the distribution of partograms and institute initiatives that encouraged midwives to use them. A follow-up survey demonstrated that this intervention led to an average increase of 28 percent in partogram use in the applicable regions. This pilot effort was part of a larger mHealth program funded by the UN Foundation and Vodafone Foundation Technology Partnership.

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Access to Health Information Electronic medical records have become a gold standard for health systems. In low- and middle-income countries, electronic records have been implemented slowly, but the introduction of mHealth can help reduce the burden on health workers and health facilities by allowing easier access to information and its sharing. For example, OpenMRS allows frontline health workers to access information from a patient’s health record using a mobile device and then add information to the health record after a consultation. ChildCount+ has been very successful in sub-Saharan Africa in enhancing the efforts of community health workers. The program offers an integrated system that links individual patient records with population data in order to improve follow-up services and better understand a community’s needs. It is important to note, however, that the literature on the outcomes and cost- effectiveness of health information applications is still limited.

The Need for Evaluation It is important to know whether the investments in time and resources in mHealth have been both impactful and cost-effective and if they are good candidates for scaling up. Despite extensive innovation in the development of mobile health technologies, evaluation of the effectiveness of these technologies has been limited, as repeatedly noted. Although some uses of mHealth appear to be successful and others appear to be promising, only a small share of all mHealth activities in low- and middle-income countries have been subjected to high-quality, rigorous evaluation. Thus, there are still very few examples of proven impact at large scale of mHealth programs.

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Looking Forward As evidence from well-planned evaluations grows, it is likely that there will be a transition from experimentation with different technologies to strategic implementation of the technologies known to be cost-effective. Moreover, as the application of mHealth continues to advance, it is clear that other issues will also need to be addressed more fully, including data privacy and ways to integrate various applications. Overall, there is hope that mHealth will offer cost- effective solutions to improving health outcomes and access to health information in low- and middle- income countries. However, it is important to note that this hope has not yet been realized at scale in ways that are based on rigorous evaluation and evidence of cost-effectiveness.

New Diagnostics for TB: Xpert MTB/RIF Although the overwhelming majority of TB deaths could be prevented with early diagnosis and proper treatment, diagnosis of TB has faced substantial challenges. First, the traditional standard for diagnosing pulmonary TB, microscopic examination of sputum samples from a TB suspect, is estimated to correctly diagnose only about 20 percent to 60 percent of adults who have TB. Second, sputum microscopy cannot be used to diagnose TB in young children, because they cannot produce sputum samples. In addition, substantial training is required for consistently accurate diagnosis of extrapulmonary TB, and even skilled clinicians experience significant variability in their results. Finally, the diagnosis of multidrug-resistant TB (MDR-TB) has required that samples be cultured, which can be done only in select laboratories and takes substantial time to produce results.

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PHOTO 18-2 There is little incentive for the private sector to invest in diagnostics for TB, because most people with TB are

poor and live in low- and lower middle-income countries. However, a number of not-for-profit organizations, like the Foundation for Innovative New Diagnostics, are working on

better diagnostics for some of the communicable diseases such as TB. This photo shows the Xpert machine, which provides a diagnostic test that WHO has recommended for the diagnosis of drug-susceptible TB and TB that is resistant to rifampicin.What steps could the global community take to further incentivize for- profit and not-for-profit companies to invest more money in the development of new diagnostics for the “unfinished agenda” of

communicable diseases?

Courtesy of The Global Fund, photo by John Rae.

In light of this situation, the global TB community has long sought improved tools for diagnosing TB, and progress has been made in this direction. In 2006, the Foundation for Innovative New Diagnostics (FIND) partnered with Cepheid Inc. and the University of Medicine and Dentistry of New Jersey to try to develop an

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enhanced diagnostic tool for TB. They sought to use existing technology to improve the sensitivity and specificity of TB detection—especially in difficult cases involving drug resistance and coinfection with HIV—all while automating the process to reduce interuser variability.

From this collaboration came the Xpert TB test. In just 2 hours, Xpert detects the presence of mycobacterium tuberculosis by amplifying and analyzing genetic material in the sputum sample. Furthermore, the technology detects resistance to the first-line drug rifampicin (RIF), which can serve as a good proxy for MDR- TB. Moreover, the Xpert MTB/RIF system offers high sensitivity and specificity compared to sputum smear microscopy, with rates of 98 percent to 100 percent and 100 percent, respectively, in individuals without HIV co-infection. In addition, clinical trials have shown that the system detects TB in individuals co-infected with HIV with a sensitivity of 70 percent, rather than the 50 percent sensitivity offered by conventional sputum smear microscopy.

FIND and the manufacturer have negotiated prices for use in low- and middle-income countries, with Xpert costing $17,000 for the permanent equipment and $9.98 for each test cartridge, instead of the standard price of $16.86. This concessional pricing is possible because organizations including the President’s Emergency Plan for AIDS Relief (PEPFAR), USAID, UNITAID, and the Bill & Melinda Gates Foundation provided financial support and negotiated a discount on each cartridge. Although the automation of Xpert means workers will no longer need to spend time examining sputum by microscopy, Xpert does require annual maintenance and is still more expensive than traditional techniques. It is expected that diagnosing a case of TB will now cost $61, about 55 percent more than when using traditional methods. The most recent assessments have shown Xpert to be “generally cost-effective.”

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WHO now recommends the use of Xpert as the initial diagnostic test for any child or adult suspected of having TB. The use of Xpert technology has increased steadily. However, recent studies suggest that the test is still substantially underutilized.

The development of the Xpert MTB/RIF test owes its success to collaboration across disciplines and organizations. Researchers developed a working technology to improve the efficiency of a common laboratory technique, and a team at the University of Medicine and Dentistry of New Jersey applied the technology to analyze TB in sputum samples. FIND aided in negotiations between funding organizations and Cepheid Inc. to reduce the price per cartridge for resource-poor countries. By bringing advanced diagnostics at reduced costs to resource-poor settings, Xpert should improve care for TB patients throughout the world. In addition, this important development has set a foundation for additional efforts in the search for better TB diagnostics.

Saving Women’s Lives: The Non-pneumatic Anti-shock Garment Postpartum hemorrhages are the largest cause of maternal death worldwide. Especially in resource-poor settings, healthcare workers may lack the training to manage labor appropriately, which can lead to improper uterine muscle tone and subsequent hemorrhage. However, a multitude of other factors also contribute to postpartum hemorrhages (PPH). Ruptured uteruses, vaginal lacerations, and retained placentas are other common causes of PPH that are difficult to manage in resource-poor settings. These problems are particularly troublesome in cases of delayed care, and reducing the rate of blood loss can have a significant effect on the clinical outcome. Thus, there is an important need for treatment of shock and prevention of blood loss among women giving birth. Anti-shock garments—which inflate to compress the

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abdomen to prevent blood loss—were developed decades ago, but their price and complexity have been barriers for adoption in low-resource settings where they might be particularly helpful.

The non-pneumatic anti-shock garment (NASG) is based on technology from the United States National Aeronautics and Space Administration (NASA). The product was developed by PATH, the University of California, San Francisco (UCSF) Safe Motherhood Program, Pathfinder International, and the Blue Fuzion Group. Rubber belts with Velcro are tightened around a mother’s abdomen to reduce bleeding while the woman is transported to a care provider as quickly as possible. The garment acts to both treat shock and shift blood toward critical organs, stabilizing the mother’s condition during delays in care. When WHO originally recommended the NASG for patients with PPH, at $170 per device, the technology was thought to be too expensive for resource-poor countries. PATH, a global health organization based in the United States, worked to make manufacturing more cost-effective, which reduced the price to just $54 for each reusable garment. The NASG has been validated in clinical trials analyzed by the UCSF Safe Motherhood Initiative in Egypt, Nigeria, Zambia, Zimbabwe, and India.

The NASG reduces bleeding by 50 percent and could reduce maternal morbidity and mortality due to hemorrhage. Indeed, in a trial in Egypt, mortality was reduced by 20 percent and morbidity by 160 percent when the NASG was applied upon obstetric hemorrhage until time of care. Delays in care happen often in low-resource settings, and the rate of bleeding of a woman who has just delivered can mean the difference between life and death. The device is composed of just rubber and Velcro attachments, so it can be employed in a variety of low-resource settings with minimal need for technical expertise and training.

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This promising garment suggests that some existing technologies can be of great use in resource-poor settings after a limited number of simplifying modifications. Inflatable pressure suits were first developed to prevent blood loss during surgery, but they were designed for use only by trained surgeons in the operating room. By developing a non-pneumatic version, UCSF researchers made it easier for untrained personnel to use and also economical for resource-poor countries to purchase. PATH further enhanced the technology by optimizing manufacturing to minimize costs. This simple garment appears likely to be able to buy precious time, in cost-effective ways, for dying mothers seeking treatment.

However, it will be important to see the extent to which the technology is adopted and over what period of time. A review was conducted in 2016 of the uptake of the device in Ethiopia, India, Nigeria, and Zimbabwe—all countries of exceptional importance to the numbers of women who suffer maternal mortality. This study suggested that there was considerable variance in the time and scale of uptake across the countries, with Ethiopia having the most rapid uptake.

Addressing Meningitis in Africa

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The Problem Until recently, there was an outbreak of meningitis A every 5 to 14 years across a belt in Africa stretching from Senegal to Ethiopia. These epidemics were caused by the Neisseria meningitidis serogroup A bacterium. This infection is exceptionally virulent. Without treatment, the case fatality rate can reach 80 percent. Even with treatment, 5 percent to 10 percent of the infected still die. Major epidemics have infected as many as 1 out of every 100 people, and the worst epidemic to date infected 250,000 people and led to 25,000 deaths.

Moreover, until the development of the new vaccine, regional governments sought to address the epidemics with a polysaccharide vaccine and antibiotics. These were partly effective. However, this vaccine was costly, conferred immunity only for 2 to 3 years, and provided little protection to young children. Thus, the economic and social costs of these meningitis epidemics were exceptionally high for the affected countries. On average, for example, families lost about a month of work when a family member fell ill with meningitis.

Taking Action Deeply concerned about these epidemics, leaders of the health sector in Africa requested that WHO assist in enabling the development of a more effective conjugate vaccine against meningitis A. Such a vaccine had been highly effective in eliminating meningitis A in western Europe. After a feasibility study, WHO joined with the NGO PATH to create the Meningitis Vaccine Project (MVP) to develop the new vaccine. The Bill & Melinda Gates Foundation provided $70 million to launch the initiative. MVP then embraced other partners, including the U.S. Food and Drug Administration; the Serum Institute of India; a Dutch biotech company, SynCo; and the U.K. National Institute for Biological Standards and Control.

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During the early stages of the partnership, the leadership of MVP sought the views of African health leaders about the profile of the desired vaccine, the price they thought they could pay for it, and the likely demand for the vaccine.

In 2005, much earlier than one would normally expect for the development of a new vaccine, a candidate vaccine was ready for testing. The vaccine turned out to be safe and much more effective than the polysaccharide vaccine. WHO gave fast-track approval to the vaccine in 2010, which was produced by the Serum Institute of India and named “MenAfriVac.”

About 25 million doses of the vaccine would be needed yearly for 10 years. In addition, African leaders had stressed the importance of keeping the price of the vaccine below $1 per dose. The Serum Institute of India ultimately set $0.40 per dose as the initial cost of the vaccine, with increases to be set for inflation.

African governments, led by Burkina Faso, rolled out the vaccine in 2010. They were assisted in this effort by WHO and its regional office for Africa and Gavi, the Vaccine Alliance. Governments wishing to participate in the program had to commit to financing half the operational costs of the program. Vaccination was phased in across the hardest-hit countries, with special attention to difficult-to-reach groups, such as nomadic and refugee groups. By 2014, 214 million people in 15 countries were vaccinated.

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Impact The vaccination program had dramatic effects. Burkina Faso, for example, reported no cases of meningitis A in the 2013 epidemic season. The same was true in target areas of Chad. There was also a 94 percent difference in meningitis infections between targeted and non-targeted areas in Chad that year. It has been estimated that the vaccine will avert 142,000 deaths and almost 300,000 disabilities over its first 10 years of use. So far, it has also shown itself to be safe.

Costs of the Program The vaccine was developed for $70 million, which is substantially below the average cost to develop a vaccine of around $350 million. It has been estimated that the vaccine between 2010 and 2013 cost almost $100 per DALY averted, which would make it a very good “buy.”

Keys to Success The evaluation of the program suggests a number of factors set the foundation for its success. The following factors were among the most important:

■ Commitment of African leaders ■ The development of a creative public–private partnership ■ Technological innovation ■ Developing the vaccine to meet local needs and ability to pay ■ Funding from the Bill & Melinda Gates Foundation ■ Financial and operational support from Gavi

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Future Challenges Despite the important successes to date, the program faces a number of potential challenges. First, it is not yet known for how long the vaccine will confer immunity. This, of course, could have an important bearing on the cost-effectiveness of the vaccine. Second is the risk that other meningitis strains will fill the void left by the elimination of meningitis A. The third would be the prospect of developing an even more heat-stable, affordable vaccine that could target all of the strains affecting Africa.

Advance Market Commitments The advance market commitment (AMC) is a financing mechanism that aims to encourage investment in the development and manufacturing of vaccines that can be sold at affordable prices in low-income countries. The AMC was devised in 2005 and further refined from 2006 to 2009. It started in 2009 and is housed at Gavi.

The need for a financing mechanism such as the AMC is based on the problem discussed earlier—the unwillingness of vaccine manufacturers to invest in newer vaccines that meet the needs of low-income countries because the manufacturers believe that the market for such vaccines will not be profitable. The high risks and high cost of such an investment ultimately leave suppliers with little incentive to produce. What’s more, even if a manufacturer did find reason to supply vaccines, these vaccines would be unaffordable for people in low-income countries at the prices at which they would have to be sold for the manufacturers to make a profit on them.

The AMC can best be thought of as a fund that will make financing available to vaccine manufacturers under certain circumstances they agree to with the AMC management. To erase uncertainties about the market for vaccines and provide an incentive to vaccine

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manufacturers to produce the needed quantities of the desired vaccines, a pool of money from donors guarantees that the manufacturer will receive a set price per dose produced, provided that the manufacturers will supply a predetermined quantity of vaccines for a certain amount of time at the agreed price.

In addition, manufacturers participating in the scheme must meet certain technical criteria for vaccine quality and safety predetermined by WHO. The AMC ensures that no single supplier receives all of the funding for a particular vaccine, thereby avoiding the possibility of a monopoly and problems of supply if a sole manufacturer could not meet its production commitments.

The first AMC pilot program for a vaccine against pneumococcal disease was adopted by a group of core donors including Italy, the United Kingdom, Canada, Norway, the Russian Federation, and the Gates Foundation and became fully operational in 2009. The decision to invest in a pneumococcal vaccine for the pilot program was made by a diverse group of experts in epidemiology and vaccine manufacturing. Gavi pledged to contribute $1.3 billion to this effort through 2015, with the hope of making the vaccine available to nearly 60 countries by this time.

Participating manufacturers must commit to supplying a share of the 200 million doses required over 10 years. Those manufacturers must sell the vaccine at or below the predetermined price of $3.50 a dose, to ensure that the vaccine is affordable in low-income countries. Gavi and the participating country, as part of their normal cofinancing arrangements, will cover the $3.50 cost. In addition, each participating manufacturer will receive a share of the $1.5 billion AMC fund, in proportion to the supply commitment. A manufacturer, for example, who supplied 20 million doses would receive one-tenth of the AMC funding, or $150 million.

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Setting an appropriate price for the pneumococcal vaccine and subsidy for manufacturers was a major challenge in devising the pilot program. This is largely due to suppliers keeping information about manufacturing costs confidential. To overcome this obstacle, outside consultants helped to assess the cost of manufacturing. The fact that the two main multinational suppliers of the pneumococcal vaccine and several emerging suppliers from India all expressed interest in participating in the AMC suggests that they find the AMC price, plus the payment of AMC funds, to be reasonably remunerative.

The large number of donor and technical organizations that worked together with Gavi and low- and middle-income country partners to develop the AMC and launch the pilot is a testimony to the widespread interest in this innovative mechanism. In addition to the donors mentioned earlier, who committed $1.5 billion to the AMC, the World Bank is providing its financial services, WHO is responsible for technical matters related to the AMC, and UNICEF is leading vaccine procurement efforts.

International Finance Facility for Immunisation The International Finance Facility for Immunisation (IFFIm) is a financing mechanism that seeks “to rapidly accelerate the availability and predictability of funds for immunization.” IFFIm funds are used by Gavi to accomplish its mission of “reducing the number of vaccine-preventable deaths and illnesses among children under 5.” IFFIm was originally launched in 2006 as a charity by the government of the United Kingdom but now includes Australia, France, Italy, the Netherlands, Norway, South Africa, Spain, and Sweden. Brazil has signaled its intent to contribute to the IFFIm as well.

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The IFFIm was created to address the lack of secure funding for immunization in low-income countries. Another issue the IFFIm seeks to address is that donors usually provide financing on a year-to-year basis, making it hard for recipient governments to plan their budgets for programs that receive assistance, such as immunization programs. The IFFIm is meant to help ensure longer-term and more predictable financing for vaccine programs.

To ensure a reliable stream of funding for Gavi, donor countries have pledged $6.5 billion over 25 years to the facility. IFFIm sells bonds to raise this money in the capital markets of high-income countries. This makes the money available immediately, without having to wait for year-to-year financing from donor governments. The donor countries repay the bonds over time, based on their initial pledges. The fact that the IFFIm is backed by the promises of these countries allows it to maintain a good credit rating and to sell bonds at rates that are acceptable to the donor countries that have to honor the bonds.

Gavi is using IFFIm funds to purchase and deliver vaccines in countries that receive its support, in addition to working with health services to strengthen immunization programs. With funding from the IFFIm, Gavi has introduced a pentavalent vaccine, which immunizes against diphtheria, pertussis, tetanus, hepatitis B, and Hib in a single vaccine. In fact, the IFFIm enabled Gavi to double its spending between 2006 and 2009. By 2014, the IFFIm had provided Gavi, for example, with $191 million to purchase stockpiles of polio vaccines for use in outbreaks, more than $1 billion for the pentavalent vaccine, and about $100 million for pneumococcal vaccine. An independent evaluation of the IFFIm estimated that the facility had helped Gavi save more than 2.1 million lives between 2006 and 2011.

With secure funding, Gavi hopes to deliver reliable aid to countries for the long term, enabling these countries to plan and implement

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immunization programs more effectively. In addition, having more secure and longer-term funding allows Gavi to purchase vaccines in bulk and at lower prices than would otherwise be possible. Thus, the IFFIm hopes to enable the purchase of more vaccines with the same amount of money.

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▶ Main Messages Science and technology have the potential to make major contributions to the development of diagnostics, vaccines, drugs, and medical devices that can help address the burdens of disease in low- and middle-income countries. Progress in scientific areas like the sequencing of genes, information technology, chemistry, robotics, and biotechnology can help, for example, to engineer mosquitoes that will not carry disease, discover new drugs much more rapidly than before, and develop less expensive and more effective vaccines.

In a more ideal world, diagnostics, vaccines, drugs, and medical devices would be appropriate to the needs of the health conditions that cause the largest burden of disease in low- and middle- income countries. They would also be appropriate to the ability of countries to manage their health systems. If these were the case, they would be affordable to low-income patients and countries that are unable to spend much on health. They would also be heat stable, not require refrigeration, and be easy to store and transport. The number of pills needed to cure a disease would be few and require a short course of therapy. Ideal vaccines would be a combination of many of the vaccines that exist today, so that children would need fewer vaccinations to be fully covered. Given the risks of injections being unsafe, the delivery devices for vaccines would increasingly rely on noninvasive means, such as nasal sprays, skin patches, or, perhaps, vaccines that are edible.

Unfortunately, the needed advances are unlikely to come about on their own. This is largely a reflection of the fact that the for-profit sector has historically been a major developer of diagnostics, vaccines, and drugs but does not believe that the market for these products in low- and middle-income countries is sufficient to give it

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an adequate return on its investment. In addition, the public sector is risk averse and would prefer to purchase a product developed by the private sector rather than to try to develop these products itself. The failure of the market is reflected, for example, in the very small number of drugs that have been developed over the last 30 years to address the main burdens of disease among the poor in low- and middle-income countries. Moreover, vaccine development is constrained by the need for substantial investments and limited capacity in an industry with a very small number of producers.

Overcoming these market failures and encouraging the development of the desired products will probably require a series of measures. Some of these can be push mechanisms that are meant to lower the cost of research and development for the private sector. These could include, for example, direct financing of research by the government, the facilitation of clinical trials by the government, or governments offering tax credits for research and development. Push mechanisms do lower the cost of research and development, but they provide no certainty that the desired product will be produced.

Another set of efforts could focus on pull mechanisms, which are intended to help assure a satisfactory return to investors in the event that a product is produced. These mechanisms could include funding mechanisms to increase the uptake of existing vaccines, prizes, transferable patents, copayments, market assurances, and tax credits for vaccine sales. Pull mechanisms have the advantage of providing funding only when the desired product is available. However, they have the disadvantage of having to be negotiated far in advance of product availability, and parties may not be satisfied with the terms of their agreement at the time in the future when the products are available.

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A mechanism already in use for vaccines and for AIDS drugs is tiered pricing. This is an arrangement in which products are sold at different prices in different markets, with the principle being that the price of sales in high-income country markets will help defray the cost of the products in low- and middle-income country markets. However, these arrangements have generally been put in place only when products were established; efforts are now under way to try to put them in place at the early stages of a product’s life.

Considerable hope for new product development is being placed in public–private product development partnerships, such as the TB Alliance, the Medicines for Malaria Venture, and the Human Hookworm Vaccine Initiative. The aim of these ventures is to bring the strengths of the public and private sectors together in complementary ways that can spur the development of new products. A number of innovative financing mechanisms have also been developed to spur product development and use. In its case studies, the chapter suggests some steps that can be taken both to develop products that are needed and to see that they are widely used once they are developed.

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Study Questions 1. What are some of the ideal properties that diagnostics,

vaccines, and drugs should have to be most appropriate to the health and health system needs of low- and middle- income countries?

2. To what extent do some of the available vaccines for the six basic antigens and the vaccination schedule for them meet the ideal?

3. What health conditions and risk factors deserve additional attention from science and technology? Why have you chosen those conditions and risk factors?

4. What are some of the specific gaps in diagnostics, drugs, vaccines, and other medical equipment that could most improve global health if filled?

5. What have been some of the major constraints to the development of drugs and vaccines that could better meet health needs in low- and middle-income countries?

6. What steps can be taken to overcome those constraints? What are the roles in this of publicly supported research? What are the roles of public–private partnerships for health?

7. Why has only 10 percent of all research expenditure worldwide focused on the diseases that most affect the poor in low- and middle-income countries? What is the 10/90 research gap?

8. What push and pull mechanisms could most help to encourage the development of new diagnostics, drugs, and vaccines?

9. What lessons does the case study on Xpert suggest for the discovery of diagnostics, drugs, and vaccines?

10. If you were in charge of the Bill & Melinda Gates Foundation, how would you spend money on research and development of new products for global health? Why?

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References 1. The World Bank. (n.d). Data: Prevalence of HIV, total (% of population ages 15–49). Retrieved from https://data.worldbank.org/indicator/SH.DYN.AIDS.ZS

2. Avert. (n.d.). HIV and AIDS in South Africa. Retrieved from https://www.avert.org/professionals/hiv-around- world/sub-saharan-africa/south-africa

3. Birn, A. E. (2005). Gates’s grandest challenge: Transcending technology as public health ideology. The Lancet, 366(9484), 514–519.

4. UNICEF. (2010). Facts for life (4th ed.). Retrieved from https://www.unicef.org/publications/files/Facts_for_Life_EN_010810.pdf

5. Gavi. (n.d.). Pentavalent vaccine support. Retrieved from https://www.gavi.org/support/nvs/pentavalent/

6. Centers for Disease Control and Prevention. (n.d.). BCG vaccine. Retrieved from http://www.cdc.gov/tb/publications/factsheets/prevention/BCG.htm

7. Global Alliance for TB Drug Development. (2006, May 24). New TB drugs urgently needed to replace treatment from the 1960s. Second Gates grant to TB Alliance quadruples initial support. Retrieved from http://www.tballiance.org/downloads/pressreleases/PR_GatesGrant_5- 23-06.pdf

8. Institute of Medicine Committee on the Economics of Antimalarial Drugs; Arrow, K. J., Panosian, C., & Gelband, H. (Eds.). (2004). The cost and cost-effectiveness of antimalarial drugs. In Saving lives, buying time: Economics of malaria drugs in an age of resistance (pp. 61–78). Washington, DC: National Academies Press. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK215621/

9. MVI. (n.d.). RTS,S. Retrieved from https://www.malariavaccine.org/malaria-and-

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

https://data.worldbank.org/indicator/SH.DYN.AIDS.ZS

https://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/south-africa

https://www.unicef.org/publications/files/Facts_for_Life_EN_010810.pdf

https://www.gavi.org/support/nvs/pentavalent/

http://www.cdc.gov/tb/publications/factsheets/prevention/BCG.htm

http://www.tballiance.org/downloads/pressreleases/PR_GatesGrant_5-23-06.pdf

http://www.ncbi.nlm.nih.gov/books/NBK215621/

https://www.malariavaccine.org/malaria-and-vaccines/first-generation-vaccine/rtss

vaccines/first-generation-vaccine/rtss 10. Land, M., Hauser, L., Jun, S. R., Nookaew, I., Leuze, M. R.,

Ahn, T. H., . . . Ussery, D. W. (2015). Insights from 20 years of bacterial genome sequencing. Functional & Integrative Genomics, 15(2), 141–161. doi: 10.1007/s10142-015-0433-4

11. World Health Organization. (2002). Genomics and world health: A report of the Advisory Committee on Health Research. Retrieved from http://whqlibdoc.who.int/hq/2002/a74580.pdf

12. Weatherall, D., Greenwood, B., Chee, H. L., & Wasi, P. (2006). Science and technology for disease control: Past, present, and future. In D. T. Jamison, J. G. Breman, A. R. Measham, et al. (Eds.), Disease control priorities in developing countries (2nd ed., pp. 119–137). New York, NY: Oxford University Press.

13. University of Notre Dame. (2014, November 27). Genomes of malaria-carrying mosquitoes sequenced. ScienceDaily. Retrieved from https://www.sciencedaily.com/releases/2014/11/141127212323.htm

14. Jiang, X., Peery, A., Brantley Hall, A., Sharma, A., Chen, X. G., Waterhouse, R. M., . . . Tu, Z. (2014). Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi. Genome Biology, 15(9). Retrieved from http://genomebiology.com/2014/15/9/459

15. Fauci, A. S. (2001). Infectious diseases: Considerations for the 21st century. Clinical Infectious Diseases, 32(5), 675–685.

16. Spilde, I. (2012). Edible vaccines can be grown everywhere. ScienceNordic. Retrieved from http://sciencenordic.com/edible-vaccines-can-be-grown- everywhere

17. Daar, A. S., Thorsteinsdottir, H., Martin, D. K., Smith, A. C., Nast, S., & Singer, P. A. (2002). Top ten biotechnologies for

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

http://whqlibdoc.who.int/hq/2002/a74580.pdf

https://www.sciencedaily.com/releases/2014/11/141127212323.htm

http://genomebiology.com/2014/15/9/459

http://sciencenordic.com/edible-vaccines-can-be-grown-everywhere

improving health in developing countries. Nature Genetics, 32(2), 229–232.

18. Grand Challenges. (n.d.). Explore awarded grants. Retrieved from https://grandchallenges.org/#/map

19. Mahmoud, A., Danzon, P. M., Barton, J. H., & Mugerwa, R. D. (2006). Product development priorities. In D. T. Jamison, J. G. Breman, A. R. Measham, et al. (Eds.), Disease control priorities in developing countries (2nd ed., pp. 139–155). New York, NY: Oxford University Press.

20. Glass, S. N., Batson, A., & Levine, R. (2006). Issues paper: Accelerating new vaccines. Geneva, Switzerland: Global Alliance for Vaccines and Immunisation.

21. Trouiller, P., Torreele, E., Olliaro, P., White, N., Foster, S., Wirth, D., & Pécoul, B. (2001). Drugs for neglected diseases: A failure of the market and a public health failure? Tropical Medicine and International Health, 6(11), 945–951.

22. Bloom, B. R., Michaud, C. M., LaMontagne, J. R., & Simonsen, L. (2006). Priorities for global research and development interventions. In D. T. Jamison, J. G. Breman, A. R. Measham, et al. (Eds.), Disease control priorities in developing countries. (2nd ed., pp. 103–118). New York, NY: Oxford University Press.

23. International Policy Network. (2004). Diseases of Poverty and the 10/90 Gap. Retrieved from https://www.who.int/intellectualproperty/submissions/InternationalPolicyNetwork.pdf

24. World Health Organization. (2014). TDR: About us. Retrieved from http://www.who.int/tdr/about/en/

25. Morel, C. M., Acharya, T., Broun, D., Dangi, A., Elias, C., Ganguly, N. K., . . . Yun, M. (2005). Health innovation networks to help developing countries address neglected diseases. Science, 309(5733), 401–404.

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

https://grandchallenges.org/#/map

https://www.who.int/intellectualproperty/submissions/InternationalPolicyNetwork.pdf

http://www.who.int/tdr/about/en/

26. Bill & Melinda Gates Research Institute. (n.d.). Bill & Melinda Gates Medical Research Institute. Retrieved from https://www.gatesmri.org/

27. World Health Organization. (2011). mHealth: New horizons for health through mobile technologies: Second global survey on eHealth. Geneva, Switzerland: Author.

28. Lewis, T., Synowiec, C., Lagomarsino, G., & Schweitzer, J. (2012). E-health in low- and middle-income countries: Findings from the Center for Health Market Innovations. Bulletin of the World Health Organization, 90, 332–340. doi: 10.2471/BLT.11.099

29. Kallander, K. (2013). Mobile health (mHealth) approaches and lessons for increased performance and retention of community health workers in low- and middle-income countries: A review. Journal of Medical Internet Research, 15(1), e17. doi: 10.2196/jmir.2130

30. Mossman, K., McGahan, A., Mitchell, W., & Bhattacharyya, O. (2014). Evaluating high-tech health approaches in low- income countries. Stanford Social Innovation Review. Retrieved from http://www.ssireview.org/blog/entry/evaluating_high_tech_health_approaches_in_low_income_countries

31. Unite for Sight. (2013). mHealth technology in global health. Retrieved from http://www.uniteforsight.org/global-health- university/mhealth

32. Colaci, D., Chaudhri, S., & Vasan, A. (2016). mHealth interventions in low-income countries to address maternal health: A systematic review. Annals of Global Health, 82(5), 922–935.

33. Hurt, K., Walker, R. J, Campbell, J. A., & Egede, L. E. (2016). mHealth interventions in low and middle-income countries: A systematic review. Global Journal of Health Science, 8(9), 183–193. doi: 10.5539/gjhs.v8n9p183

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

https://www.gatesmri.org/

http://www.ssireview.org/blog/entry/evaluating_high_tech_health_approaches_in_low_income_countries

http://www.uniteforsight.org/global-health-university/mhealth

34. World Health Organization. (2018). Tuberculosis. Key Facts. Retrieved from https://www.who.int/news-room/fact- sheets/detail/tuberculosis

35. Steingart, K. R., Ng, V., Henry, M., Hopewell, P. C., Ramsay, A., Cunningham, J., Urbanczik, R., . . . Pai, M. (2006). Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: A systematic review. The Lancet Infectious Diseases, 6(10), 664–674. doi: 10.1016/S1473-3099(06)70602-8

36. World Health Organization. (2010). Frequently asked questions on Xpert MTB/RIF assay. Retrieved from http://www.who.int/tb/laboratory/xpert_faqs.pdf

37. World Health Organization. (2016). Tuberculosis diagnostics: Automated real-time DNA amplification test for rapid and simultaneous detection of TB and Rifampicin resistance: Xpert MTB/RIF assay. Retrieved from https://www.who.int/tb/publications/factsheet_xpert.pdf? ua=1

38. Blakemore, R., Story, E., Helb, D., Kop, J., Banada, P., Owens, M. R., . . . Alland, D. (2010). Evaluation of the analytical performance of the Xpert MTB/RIF assay. Journal of Clinical Microbiology, 48(7), 2495–2501. doi: 10.1128/jcm.00128-10

39. Theron, G., Peter, J., van Zyl-Smit, R., Mishra, H., Streicher, E., Murray, S., . . . Dheda, K. (2011). Evaluation of the Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in a high HIV prevalence setting. American Journal of Respiratory and Critical Care Medicine, 184(1), 132–140. doi: 10.1164/rccm.201101-0056OC

40. Piatek, A. S., Van Cleeff, M., Alexander, H., Coggin, W. L., Rehr, M., Van Kampen, S., . . . Mukadi, Y. (2013). GeneXpert for TB diagnosis: Planned and purposeful implementation.

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

https://www.who.int/news-room/fact-sheets/detail/tuberculosis

http://www.who.int/tb/laboratory/xpert_faqs.pdf

https://www.who.int/tb/publications/factsheet_xpert.pdf?ua=1

Global Health: Science and Practice, 1(1), 18–23. doi: 10.9745/ghsp-d-12-00004

41. Schito, M., Peter, T. F., Cavanaugh, S., Piatek, A. S., Young, G. J., Alexander, H., et al. (2012). Opportunities and challenges for cost-efficient implementation of new point-of- care diagnostics for HIV and tuberculosis. Journal of Infectious Diseases, 205(Suppl. 2), S169–S180. doi: 10.1093/infdis/jis044

42. Meyer-Rath, G., Schnippel, K., Long, L., MacLeod, W., Sanne, I., Stevens, W., . . . Dowdy, D. W. (2012). The impact and cost of scaling up GeneXpert MTB/RIF in South Africa. PLoS One, 7(5), e36966. doi: 10.1371/journal.pone.0036966

43. World Health Organization. (2013). Using the Xpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and rifampicin resistance in adults and children. Expert Group Meeting Report 2013. Geneva, Switzerland: Author.

44. Cazabom, D., Tripti Pande, T., Kirk,, S., Van Gemert, W., Sohn, H., Denkinger, C., . . . Pai, M. (2018). Market penetration of Xpert MTB/RIF in high tuberculosis burden countries: A trend analysis from 2014–2016. Gates Open Research. Retrieved from https://gatesopenresearch.org/articles/2-35/v2

45. Helb, D., Jones, M., Story, E., Boehme, C., Wallace, E., Ho, K., . . . Alland, D. (2010). Rapid detection of mycobacterium tuberculosis and rifampin resistance by use of on-demand, near-patient technology. Journal of Clinical Microbiology, 48(1), 229–237. doi: 10.1128/jcm.01463-09

46. Mourad-Youssif, M., Ojengbede, O., Meyer, C., Fathalla, M., Morhason-Bello, I., Galadanci, H., . . . Miller, S. (2010). Can the non-pneumatic anti-shock garment (NASG) reduce adverse maternal outcomes from postpartum hemorrhage?

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

https://gatesopenresearch.org/articles/2-35/v2

Evidence from Egypt and Nigeria. Reproductive Health, 7(1), 24.

47. Miller, S., Martin, H. B., & Morris, J. L. Anti-shock garment in postpartum haemorrhage. Best Practice & Research Clinical Obstetrics & Gynaecology, 22(6), 1057–1074. doi: 10.1016/j.bpobgyn.2008.08.008

48. Vahedi, M., Ayuyao, A., Parsa, M., & Freeman, H. (1995). Pneumatic antishock garment-associated compartment syndrome in uninjured lower extremities. Journal of Trauma, 384(4), 616–618.

49. World Health Organization. (2011). Non-pneumatic anti-shock garment. Retrieved from http://www.who.int/medical_devices/innovation/new_emerging_tech_30.pdf

50. ZOEX NIASG. (n.d.). Zoex non-inflatable anti-shock garment. Retrieved from http://www.zoexniasg.com/

51. PATH. (n.d.). Postpartum hemorrhage kills more new mothers than any other cause, but antishock garments can save lives. Retrieved from http://www.path.org/projects/antishock- garment.php

52. Bixby Center for Global Reproductive Health. (n.d.). Preganancy and childbirth. Retrieved from http://bixbycenter.ucsf.edu/research/safe_motherhood.html

53. Sutherland, T., Downing, J., Miller, S., Bishai, D. M., Butrick, E., Fathalla, M. M., . . . Kahn, J. G. (2013). Use of the non- pneumatic anti-shock garment (NASG) for life-threatening obstetric hemorrhage: A cost-effectiveness analysis in Egypt and Nigeria. PLoS One, 8(4), e62282. doi: 10.1371/journal.pone.0062282

54. Jordan, K.,, Butrick, E., Yamey, G., & Miller, S. (2016). Barriers and facilitators to scaling up the non-pneumatic anti- shock garment for treating obstetric hemorrhage: A qualitative

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

http://www.who.int/medical_devices/innovation/new_emerging_tech_30.pdf

http://www.zoexniasg.com/

http://www.path.org/projects/antishock-garment.php

http://bixbycenter.ucsf.edu/research/safe_motherhood.html

study. PLoS One, 11(3), e0150739. doi: 10.1371/journal.pone.0150739

55. This case is based on Glassman, A., Temin, M., & the Millions Saved Team and Advisory Group. (2016). Beginning of the end: Eliminating meningitis A across Africa’s meningitis belt. In A. Glassman, M. Temin, & the Millions Saved Team and Advisory Group (Eds.), Millions Saved (pp. 13–22). Washington, DC: Center for Global Development. Those interested in a more complete account of the case and additional references will want to read the case in Millions Saved.

56. Cernuschi, T., et. al. (2011). Advance market commitment for pneumococcal vaccines: putting theory into practice. Bulletin of the World Health Organization, 89, 913–918. doi: 10.2471/BLT.11.087700

57. Gavi. (n.d.). How the pneumococcal AMC works. Retrieved from https://www.gavi.org/funding/pneumococcal- amc/how-the-pneumococcal-amc-works/

58. Gavi. (n.d.). Pneumococcal AMC. Retrieved from http://www.gavi.org/funding/pneumococcal-amc/

59. IFFIm. (n.d.). Homepage. Retrieved from http://www.iff- immunisation.org

60. IFFIm. (n.d.). Overview. Retrieved from http://www.iffim.org/about/overview/

61. Gavi. (n.d.). International finance facility for immunisation. Retrieved from https://www.gavi.org/funding/iffim/

62. IFFIm. (2013). The International Finance Facility for Immunisation (IFFIm). Retrieved from http://www.iffim.org/Library/Publications/Factsheets/The- International-Finance-Facility-for-Immunisation-(IFFIm)-- Brochure/

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

https://www.gavi.org/funding/pneumococcal-amc/how-the-pneumococcal-amc-works/

http://www.gavi.org/funding/pneumococcal-amc/

http://www.iff-immunisation.org

http://www.iffim.org/about/overview/

https://www.gavi.org/funding/iffim/

http://www.iffim.org/Library/Publications/Factsheets/The-International-Finance-Facility-for-Immunisation-(IFFIm)--Brochure/

63. IFFIm. (n.d.). Results. Retrieved from http://www.iffim.org/funding-gavi/results/

C op

yr ig

ht ©

2 01

9. J

on es

& B

ar tle

tt Le

ar ni

ng , L

LC . A

ll rig

ht s

re se

rv ed

http://www.iffim.org/funding-gavi/results/