Technology innovation for infectious diseases in the developing world

Bridging the gulf between markets and disease endemicity

By deaths and DALYs, the focus on HIV/AIDS, tuberculosis and malaria on the global health landscape is understandable: the “Big Three” diseases account for over 4.3 million deaths per year[19]. While the burden of disease falls disproportionately still on low- and middle-income countries, there remains a significant paying market in industrialized countries as well. Boosted by public funding for these diseases, private sector interest is also correspondingly greater.

In a survey of R&D projects focused on neglected diseases, BioVentures for Global Health found 218 R&D projects on AIDS, tuberculosis and malaria--over four times the number of projects on diarrheal diseases (including rotavirus, cholera, typhoid fever, shigellosis, enterotoxigenic E. coli) and pneumococcal disease. By contrast, these other diseases of poverty, specifically various causes of diarrheal disease and pneumococcal infection, claim 3.8 million deaths each year[20]. The number of projects cannot tell the full story: the state-of-the-art and the technical feasibility of next steps vary by disease. Still the difference should provoke reflection on how priorities are set.

Traditional distinctions among Type I diseases (those endemic in both North and South, but with a sizable paying market in the North) and Type II diseases (also endemic globally, but disproportionately so in developing countries, such as AIDS and tuberculosis) and Type III diseases (endemic only in developing countries) depend on the size of potential paying markets for these diseases. Such distinctions may help bound likely contributions and interest from the private sector in these areas of pharmaceutical discovery and R&D. Where there are no paying markets, market failures result.

Bridging this gulf, public sector investments can play an important role in driving this innovation. Between 2007 and 2010, the G-Finder survey found that 97 percent of the research funding backing neglected disease research projects originates from high-income countries[21]. Nearly 64 percent of all funders’ monies comes from the United States. Most publicly funded product development partnerships concentrate their missions around a unifying disease and technology focus, but alternative approaches spanning a cluster of diseases raise the prospect of sharing a common technology platform.

As a market, emerging economies have caught the attention of the global pharmaceutical industry. On the one hand, the industry eyes the growing middle and upper classes of these emerging economies as potential paying customers. On the other hand, 960 million of the bottom billion in the world live in middle-income countries. This is in sharp contrast to two decades ago when over 90 percent of the poorest of the poor lived in low-income countries. Most of these poor people live in countries such as India, Pakistan, Indonesia, and Nigeria, which have graduated from low- to middle-income status[22].

This has implications for pharmaceutical innovation and access. For example, in establishing tiering schemes that give preferential access, from licensed technology to product prices, this tension has made firms reluctant to offer such breaks to middle-income countries. This is reflected in the challenges that the Medicines Patent Pool faces in recruiting companies to license voluntarily their HIV/AIDS drugs for generic production as part of fixed-dose combinations. Similarly, the anchoring of the GlaxoSmithKline-initiated Pool for Open Innovation Against Tropical Neglected Diseases and WIPO Re:Search Consortium--both efforts to pool building blocks of knowledge and to license them royalty-free to those working on neglected diseases--places limits on geographic coverage to only least developed countries as a starting condition.

This underscores the different circumstances facing emerging economies and other developing countries. The stark reality is that less than a quarter of all biomedical research publications and less than a third of all clinical trials in Africa even relate to diseases that comprise nearly 50 percent of the burden of disease on the continent[23]. The same study found that both the research institutions most productive in publishing journal articles and filing patents were concentrated in a few countries in Africa (notably South Africa, Nigeria and Egypt). Examining patterns of collaboration on biomedical publications, over three-quarters of these journal articles were co-authored with collaborators, but only 5.4 percent engaged institutions in more than one African country while the preponderant majority of articles involved collaborators in Europe or the United States. This pattern of collaboration, in part, motivated the formation of the African Network for Drugs and Diagnostics Innovation, with its focus on intra-African coordination and collaboration on R&D.

Opportunity of technology innovation under resource-constrained settings

Mobilizing public and private sector resources, product development partnerships (PDPs) have stepped in to address the market’s failure to bring forward treatments for neglected diseases. A study of 63 neglected disease projects at the end of 2004 tells an interesting story[24]. Half of these projects were conducted by multinational firms, invariably on a “no profit-no loss” basis. Projects from the other half were conducted on a commercial basis by small-scale entities: small and medium enterprises, developing country firms and academic research institutions. Arguably, these groups viewed the opportunity costs quite differently than did the multinational corporations. This may be an important insight in targeting incentives for companies to help overcome the market’s failure.

A survey of product developers engaged in drug and vaccine R&D for neglected diseases suggested, however, that only 40 percent of such projects involved a PDP[25], with the majority going forward without a PDP partner. These included strong involvement of academic institutions, particularly in the study of neglected tropical diseases. Less than 3 percent of biotechnology companies globally participate in neglected disease R&D, but this still comes to more than 100 firms. Thirteen of the twenty largest pharmaceutical companies are involved in such projects. Multinational drug firms have also begun to shift their patterns of R&D, with recent boosts in approvals of new drugs targeting orphan diseases[26]. In some respects, orphan diseases and neglected diseases may be two sides of the same coin. By value, both face small markets: orphan diseases with small numbers of patients, but treatments that may command high prices in industrialized countries; neglected diseases with millions of patients, but hopes for very low cost treatments per episode. Facing the looming cliff of patent expirations, some of these firms might also be seeing the opportunity costs of smaller markets differently than in the past.

Emerging economies may play an increasingly strategic role in this space. Already India and China are making significant investments in domestic R&D efforts. Among BRICS countries (Brazil, Russia, India, China, and South Africa), foreign assistance to other developing countries has risen at near double-digit rates from 2005 to 2010[27].

For Brazil, health has been a significant component of the country’s foreign assistance budget. Brazil contributed approximately US$130 million to WHO and PAHO between 2005 and 2009[28] and pledged US$20 million to the Global Alliance for Vaccines and Immunizations over a twenty-year period[29]. Brazil also provided over US$37 million to UNITAID between 2006 and 2011; and in May 2011, Brazil enacted a law that donates US$2 to UNITAID per international flight, a contribution estimated to grow into a US$12 million commitment annually[30]. Brazil has also initiated a public-private partnership to transfer ARV production technology to Mozambique[31]. Together with the government of Mozambique and the Vale Foundation (the philanthropic arm of a Brazilian mining firm with operations in Mozambique), Brazil’s Institute of Technology in Pharmacos (Farmanguinhos) provided US$23 million to help build an ARV manufacturing plant[32]. Once operational, the plant will produce five ARV drugs and other pharmaceuticals, including a pain reliever and a drug for high blood pressure. In another example of South-South technology transfer, Farmanguinhos, with the Indian drug manufacturer Cipla, also partnered with the Drugs for Neglected Diseases Initiative (DNDi), a product development partnership, to bring to market a new fixed-dosed artemisinin-based combination treatment, ASMQ, the first ACT with a three-year shelf life in tropical climates[33]. Farmanguinhos and Cipla agreed in 2008 to manufacture and provide ASMQ to the public sector in developing countries at cost (with a target price of US$2.50 per full adult treatment).

Technology innovation in disease-endemic countries

Innovation for neglected diseases, more often than not, is viewed less as an exemplar to emulate and more as an exception. Just because pharmaceutical and biotechnology firms contribute to neglected disease projects, some might argue that this does not translate to new models of R&D collaboration from which broader, more generalizable lessons might be derived for more commercially viable therapeutic areas.

The perception is, by value, that markets in LMICs are considered small; and the diseases, are typically classified as Type II or III. After all, over three-quarters of global expenditures on pharmaceuticals are spent on 16 percent of the world’s population living in high-income countries[34]. However, the patent cliff faced by multinational pharmaceutical firms, the burden of non-communicable diseases requiring treatment in low- and middle-income countries, the availability of public sector funding and philanthropic capital, and the growing footprint of indigenous innovation in the pharmaceutical sector of emerging economies might prompt rethinking this view.

Spurred initially by the struggle for affordable medicines to treat HIV/AIDS, a decade-long policy process--beginning with the WHO’s Commission on Intellectual Property, Innovation and Public Health[35], continuing with the World Health Assembly’s adoption of the Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property[36], and leading up to the recently released recommendations of the WHO’s Consultative Expert Working Group on Research and Development: Financing and Coordination[37] —has sought to reshape the way in which health technologies come to market in resource-limited settings.

Several developments may shape and nurture the direction this approach to innovation emerging from developing countries takes. Important elements of this enabling environment include 1) access to building blocks of knowledge; 2) strategic use of intellectual property and innovative financing to meet public health goals; 3) collaborative norms of open innovation; and 4) alternative business models, some with a double bottom line.

Access to the building blocks of knowledge is key to innovation and technology transfer. Journal subscription costs pose barriers to accessing the latest developments in research. In response, WHO has supported the Health InterNetwork Access to Research Initiative (HINARI). Working with publishers, HINARI provides tiered access to journal articles for low- and middle-income countries. This approach has been imperfect, with all BRICS countries, Indonesia, Thailand and other middle-income countries ineligible for the discounted subscription arrangements despite sizable poor populations and under-resourced research institutions in these countries.

While such voluntary agreements provide work-around solutions to improved access to the research literature, industrialized countries have made significant strides to advancing an open access model for sharing journal publications. Departing from the traditional model of subscription-supported publication, open access journals raise revenues from other sources, ranging from endowments and membership dues to advertising and upfront submission or publication fees. As a result, published articles in open access journals are made available freely on-line without subscription barriers. A growing number of leading universities, from Harvard University to the Massachusetts Institute of Technology, have also established institutional, open access repositories where faculty may deposit their publications. Funders like the NIH and the Wellcome Trust have taken steps to require grantees to make available their journal publications in publicly accessible archives. The model of open access publication not only may have more universal applicability, both North and South, but also enables users to assemble relevant publications from multiple journals, without the barrier of subscription costs to each journal.

The past decade has witnessed shortfalls in the supply of influenza vaccine to meet the H1N1 pandemic and heightened concerns over the spread of emerging infectious diseases like SARS and avian flu. Not wishing to be last in queue for a vaccine or treatment, developing countries have sought assurances from WHO’s Global Influenza Surveillance and Response System (GISRS) that the sharing of virus samples would result not just in vaccines for industrialized countries, but also affordable access for such technologies in their settings as well. The Pandemic Influenza Preparedness Framework lays out a standard material transfer agreement, a system for benefit sharing and for contributions from pharmaceutical manufacturers and public health researchers, and hortatory measures encouraging Member States to urge manufacturers to set aside vaccines for influenza strains with pandemic potential for stockpiling and use by developing countries, to engage in technology transfer efforts, and to make such vaccines and antivirals available under tiered pricing arrangements[38]. Whether these measures will suffice in the event of a pandemic will surely be tested in the years ahead.

Anticipating the need to scale up this technology, WHO has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or enhance their capacity to produce pandemic influenza vaccine. The Netherlands Vaccine Institute was not only enlisted to provide training, but also to support an influenza vaccine technology platform or hub to facilitate the transfer of technology to these countries. Building upon a “robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production,” next steps are being planned for work under this technology platform[39]. Such technology platforms might be potentially developed for other diagnostic and therapeutic areas to accelerate innovation.

The strategic management of intellectual property rights is central to securing access to these building blocks of knowledge[40]. Even when publicly funded, patented inventions may not be easily accessible by other researchers or for use in disease-endemic countries. There may be even less incentive to share when such inventions are proprietary and privately funded. However, especially in the neglected disease space, both tiering and pooling arrangements have afforded greater access to needed research inputs. By tiering, preferential discounts or even royalty-free access to research inputs is provided, often bounded by field of use or geography. For AIDS drugs and many vaccines, tiered pricing arrangements offer price breaks to resource-limited countries. Further upstream, many neglected disease projects benefit from tiered licensing arrangements, whereby access to compounds otherwise inaccessible due to their proprietary nature is provided. The R&D pathway for repurposing existing drugs can be shortened considerably when such access is coupled with pre-clinical and even clinical data on these compounds. Under pooling arrangements, the transaction costs of bringing together needed inputs for research are lowered and cross-licensing enabled.

With varying degrees of resulting access and other forms of success, a patchwork of ad hoc tiering and pooling arrangements have emerged. Both policy instruments have their place in ensuring broader access to research inputs. Collaborating with the Medicines for Malaria Venture, GlaxoSmithKline’s release of the chemical structures and assay data of over 10,000 compounds with activity against the malaria parasite, Plasmodium falciparum, is such an example. This deposit into the pool of the European Bioinformatics Institute’s ChEMBL database and the U.S. NIH PubChem database provides wide access under a Creative Commons CC0 license (work dedicated to the public domain with waiver of copyright)[41]. Tiering and pooling often work in tandem. The Medicines Patent Pool, the Pool for Open Innovation Against Neglected Tropical Diseases, and the WIPO Re:Search Consortium all represent pooling arrangements, each with different tiered access conditions on inputs into the pool. Some work by aggregating research inputs upstream in the R&D pipeline, and others recruit patented drugs downstream in the R&D pipeline. For example, the Medicines Patent Pool’s mission is to secure voluntary licenses from pharmaceutical companies of HIV/AIDS drugs that might be used in new fixed-dose combinations or pediatric formulations. In so doing, the generic licensing of such combinations is meant to stir greater competition and thereby innovation and affordability of such treatments. Negotiating licenses, limited by field and geography, has proven challenging. To date, the only license with a company for AIDS medicines has been with Gilead. This license restricts manufacturing to India, but extends access to resulting products to a wider range of countries (though still excluding several middle-income countries) than under previous arrangements[42].

As with open access initiatives, funders can set norms supportive of sharing knowledge and also lower the risks of crossing the valley of death from pre-clinical to clinical testing. The NIH recently launched the National Center for Advancing Translational Sciences (NCATS). Created to “catalyze the generation of innovative methods and technologies” that might bring diagnostics and therapeutics to first-in-human trials, NCATS provides a spectrum of intramural and contracted services that enable small firms and academic research institutions to secure needed preclinical support[43]. Funders can also invest their philanthropic capital in ways to ensure more affordable access in exchange for non-diluting cash for biotechnology start-up companies. With Gates Foundation support, the University of California, Berkeley extended co-exclusive licenses for the microbial synthesis of artemisinin--a key antimalarial drug--to Amyris Biotechnologies and the Institute for One World Health[44]. The University made the license royalty-free for malaria indications in exchange for Amyris Biotechnologies’ commitment to produce artemisinin at no profit for treating malaria in the developing world. Amyris, in return, also received substantial philanthropic capital support (US$12 million) from the Gates Foundation. This enabled Amyris to develop proof of concept on its microbial synthesis process, which also has a dual market application for synthesizing biofuels.

Establishing collaborative norms of open innovation has deep roots in public sector funding of science. The Wellcome Trust and the U.S. National Institutes of Health (NIH) engaged leading centers involved in the Human Genome Project to agree to the Bermuda Rules, whereby investigators pledged to deposit gene sequences of every 1000 base pairs within 24 hours of completion into GenBank[45]. The intent was not only to encourage sharing of data, but also to prevent unnecessary patenting through defensive publishing. NIH has also issued guidance to grantees for the “timely release and sharing of final research data” for others to use[46] and for minimizing unnecessary encumbrances on the dissemination of publicly funded research tools[47].

Increasingly, the pharmaceutical sector has recognized the value of open innovation[48]. From Merck’s early efforts to place expressed sequence tags into the public domain to corporate participation in the Single Nucleotide Polymorphisms Consortium, pharmaceutical firms have understood the need to harness ideas from outside their walls to fuel in-house R&D innovation. The potential application for open innovation is most evident for emerging infectious diseases, where the patenting process might be outpaced by the speed of a spreading pandemic. The need for pooling patents on SARS to enable non-exclusive licensing anticipated the potential problems of intellectual property holdings on developing a diagnostic or treatment for the illness. However, the SARS epidemic came and went before the patent pool could be launched, highlighting the potential value of open innovation norms for emerging diseases.

Taking this a step further, fledgling efforts to conduct open source innovation in biomedicine have also begun. By contrast, open source innovation involves openness and transparency with the goal of shared research collaboration, but also prevents third parties from acquiring proprietary rights over what is generated by the community. Notably, India’s Council for Scientific and Industrial Research has embarked on the Open Source Drug Discovery (OSDD) initiative, initially focused on TB drugs. Using a web-based platform, hundreds of volunteers at a network of universities, both in India and elsewhere, have collaborated on re-annotating the Mycobacterium tuberculosis genome. Their collective efforts made this possible in just four months. Supported with government funding, participants submit projects for open peer review, contribute to on-line efforts under a system of microattribution, and agree to sharing their work under a click-wrap license. In not pursuing a conventional path to drug discovery, OSDD hopes to “bring down the cost of drug discovery significantly by knowledge sharing and constructive collaboration” and “to discover new chemical entities and to make them generic as soon as they are discovered, thus expediting the process of drug discovery”[49].

Summary

For many neglected diseases, the case for an alternative business model is clear. On the demand side, the need to provide affordable health technologies responsive to public health needs and the local context of low- and middle-income countries is urgent. On the supply side, high volume, closer to marginal cost pricing might match this need. Fortunately, there is growing capacity among developing countries to respond. Developing country vaccine manufacturers already supply 64 percent of vaccines procured by UNICEF[50]; and more than 80 percent of annual purchase volumes of antiretroviral drugs destined for low- and middle-income countries come from Indian generic manufacturers[51].

Bridging the supply and demand side, there is need for a more efficient model for R&D innovation. This will likely require innovation of both products and processes. Described by various names, the idea of jugaad innovation, a Hindi word meaning “an innovative fix; an improvised solution born from ingenuity and cleverness; resourceful” captures, in part, the spirit of such efforts[52]. Others have applied the descriptor, “frugal innovation”[53]. However, it is important not to connote that such innovation will come as a quick fix. Nor will it come out of a sense of thriftiness alone, without a deeper understanding of the effective use of resources. The enabling conditions for such innovation must be carefully cultivated and nurtured, and this may require piloting new models for collaborative R&D efforts--sharing resources, risks and rewards more effectively[54].

Working under the constraints of a resource-limited environment, such innovation must be resource-effective, but not substandard. This efficient use of resources is reflected in the Innovation Efficiency Index scoring of countries like China and India compared to developed countries. This index compares outputs from innovation against the constraint of available inputs for innovation in a country, and by this measure, China and India come out first and second in the world[55]. Perhaps fittingly, some have suggested that such innovation embraces Mahatma Gandhi’s tenet of getting “more from less for more people,”[56] best captured in his quote: “Earth provides enough to satisfy every man’s need, but not every man’s greed”[57].

The enabling environment for resource-effective innovation will likely accelerate not only health technologies for infectious diseases, but also for the growing burden of non-communicable diseases. Technologies like echocardiography have clinical value whether the valvular heart disease traces to rheumatic fever, drugs or atherosclerosis. The process of technology transfer, the clinical trial platforms, and the training of scientists also build towards the common purpose of bringing these new health technologies from bench to bedside.

What is exciting for global health is that the world--both North and South--has much to benefit from these new approaches to innovation. Under increasing budget constraints themselves, industrialized countries might welcome cost-effective interventions born out of the genius of innovation under resource constraint. Such innovation might be potentially disruptive, in that a product targeted at the base of the economic pyramid--an initial market marginalized by competitors--might migrate “up market” displacing established technologies[58]. From point-of-care diagnostics to more affordable drugs and vaccines, the necessity to bring more appropriate and affordable health technologies may indeed spark a new approach to innovation.