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Appendix F Commissioned PaPer Sharing Knowledge for Global Health Anthony D. So, MD, MPA, and Evan Stewart, BA* The U.S. Commitment to Global Health identifies technological innovation and diffusion as the main drivers for improving health for all people by reducing avoidable disease, disabilities, and deaths. The sharing of knowledge is central to that vision, but involves far more than making a journal article open access, posting a database publicly to the web, or licensing a technology. These are all important building blocks to transferring technology effectively. Sharing, as opposed to transferring, implies a two-way street. This is not to say that such exchanges are not asymmetric. Such exchanges slope along the steep gradients of disparities that separate industrialized and developing coun - tries. Though only one-fifth of the world’s population, the developed world is home to over two-thirds of the world’s researchers, commands three-quarters of the gross expenditure on R&D, and originates over ninety percent of the patents granted by the patent offices in Europe, the United States, and Japan. The United States alone generates nearly twice the number of scientific publications (32.7% of the world total) than the whole of the developing world (17.3%). 1 These asymmetries, of course, run in the other direction when examining *Anthony D. So, MD, MPA, is with the Program on Global Health and Technology Access and the Center for Strategic Philanthropy and Civil Society, Terry Sanford Institute of Public Policy, Duke University and the Duke Global Health Institute, Durham, North Carolina. Evan Stewart, BA, is with the Program on Global Health and Technology Access, Terry Sanford Institute of Public Policy, Duke University, Durham, North Carolina. This paper is made available as an open-access document distributed under the terms of the Cre - ative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited. 

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 THE U.S. COMMITMENT TO GLOBAL HEALTH where the global burden of disease falls. Increasingly, biomedicine is turning to the growing pools of talent in the developing world. The conduct of clinical trials is burgeoning in the developing world—no doubt lured, in part, by reports that a top-notch academic center in India charges a tenth per case report of what a second-tier medical center in the United States would in mounting a clinical trial.2 Pharmaceutical firms in the developing world may face different opportu - nity costs than large multinational corporations, and this may lead to gap-filling R&D investments, such as in more cost-effective processes for producing drugs. Shin Poong, a Korean firm that significantly lowered the costs of producing praziquantel, a drug to treat schistosomiasis, is a case in point. 3 Some of these asymmetries are eroding away. From 2000 to 2006, the average annual growth rate in the number of patent filings originating from countries such as China and India outstripped that of all reported countries in Europe and North America. 4 But the vibrancy of the scientific enterprise is only captured, in part, by tradi- tional measures of innovation. Scientists trained, publications, patent filings, and revenues from health technologies highlight the disparities, but not the potential of research collaboration. Combination drugs effective for treating malaria may be produced by Northern pharmaceutical companies, but a core component is artemisinin, a Chinese traditional medicine. Without the collaboration of research centers in countries where SARS was endemic, the race to contain the threatening pandemic would have been crippled. Without the wild virus samples of avian flu from developing countries, steps to preparing a vaccine stockpile would slow. The interdependency of global health is clear from such examples. But these examples also underscore the importance of sharing knowledge for global health and of shaping effectively the enabling environment for doing so. What should be the focus of the U.S. commitment to global health—level- ing the slope or ensuring the flow of knowledge on that two-way street? Perhaps solutions need to address both. In a globalizing world, both knowledge and the human resources capable of applying that knowledge flow readily across borders. If the process of sharing knowledge only lures away the most talented to U.S. research laboratories, would it only exacerbate the brain drain from developing countries? If those from developing countries train here in the United States, will they return to settings where they can apply those skills? If the governance of product development partnerships represents the voices of donors but not those they purport to serve in developing countries, will the fruits of their work be effectively disseminated? As a recent study observed, U.S.-based companies increasingly have sponsored clinical trials in developing countries, but of the cur- rent Phase III clinical trials in these settings, not one in their sample focused on a disease endemic largely in developing nations.5 Is it really ethical or sustainable to mount clinical trials in developing countries that yield new treatments, but to fail to make these therapies affordable or more targeted to the public health needs of the populations in which they were tested? Sharing knowledge in the context of the U.S. commitment to global health often emphasizes the North-South axis of collaboration. From the vantage point

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 APPENDIX F of the United States, the potential for collaboration and capacity building to improve global health is greatest along this axis. Of course, there are lessons from years of North-North collaborations across countries that might cross-apply. Not to overlook other axes though, South-South collaborations deserve particular note. The INDEPTH Network consists of 34 demographic surveillance sites in 18 countries, all in the developing world.6 Facilitating cross-site studies of longi- tudinal health and social studies in resource-limited settings, the network draws support from a range of Northern donors, including private foundations such as Gates, Rockefeller, the Wellcome Trust, and Hewlett; bilateral aid agencies such as CIDA, DFID, and Sida; and government research agencies such as IDRC and the U.S. National Institutes of Health (NIH). With its Secretariat based in Accra, Ghana, the network’s governance remains largely in the hands of researchers from developing countries. Partnerships though are welcomed with Northern institutions, from product development partnerships such as the Malaria Vaccine Initiative to universities such as the London School of Hygiene and Tropical Medicine and the Swiss Tropical Institute. The rise of modern medicine has introduced another important dimension of knowledge sharing—the bidirectional exchange between industry and publicly funded institutions such as universities and government laboratories. Dispropor- tionate to the level of corporate funding, the norms governing this exchange have reshaped the way universities share their inventions. Some have suggested that the commercialization of university research has corrupted the mission of higher education.7,8 Many of these concerns trace to the nature of the agreements struck between universities and corporations. These contracts affect the publishing of research, the sharing of data and research tools, and the licensing of patented inventions. Corporations bring complementary expertise, an ability to scale up products for delivery, and additional research resources. While such collabora - tions may bring value to university research efforts, the conditions under which they operate deserve greater scrutiny and transparency. Society has relied on the academy to contribute to knowledge in the public domain, to maintain the inde - pendence of inquiry with safeguards against conflict of interest, and to engage in “blue-sky” research and high-risk experimentation. The market has failed to deliver diagnostics, drugs, and vaccines that meet the disproportionate burden of disease afflicting those in developing countries. Public-private partnerships have emerged over the past decade to fill this gap. Using public sector monies, product development partnerships have embarked on drug discovery programs for neglected diseases. Half of these partnerships involved multinational corporations that conducted these projects on a “no profit- no loss” basis. Of note though, the other half of these projects were conducted by small firms doing so on a commercial basis.9 The opportunity costs for these smaller firms may be different. There can be an important North-South dimension to these collaborations as well. A recent survey found that over half of private sector firms in health biotechnology in developing countries had ongoing col - laborations with partners in developed countries.10

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0 THE U.S. COMMITMENT TO GLOBAL HEALTH STEPS TO SHARING KNOWLEDGE FOR GLOBAL HEALTH Sharing knowledge for global health involves generating knowledge relevant to the context of low- and middle-income countries, effectively transferring such knowledge and technologies to these settings, and ensuring that its intended ben - eficiaries can apply it on a sustained basis. Each of these steps presents its own set of challenges, but also affords new opportunities. Knowledge must either be relevant or adapted to the context of low- and middle-income countries. Some of this knowledge will be relevant because the health problems are shared ones between North and South. Often thought to be diseases of affluence, noncommunicable diseases, in fact, comprise a growing share and already account for nearly half of the burden of disease in developing countries.11 Put in perspective, cardiovascular diseases, cancers, and diabetes comprise 16% of the burden of disease in low- and middle-income countries. By comparison, malaria is responsible for 4% of the disability-adjusted life years lost in these countries.12 As the 10/90 gap suggests though, the investment in global health R&D does not prioritize efforts focused on the burden of disease that disproportionately afflicts those in low- and middle-income countries. With the paying market being relatively small, some treatments rely on the spillovers from dual markets. The availability of eflornithine, the “resurrection drug” for treating sleeping sickness, has at times depended on its dual use as a treatment for the removal of facial hair in women. For those engaged in biodefense research, substantive review usually focuses on the dual use of such technologies for biodefense against emerging infections as well as for potentially nefarious purposes.13 Some of this research, including the platform technologies applied, might be evaluated for a third use—humanitarian applications to neglected diseases in developing countries. Not relying on the serendipity of finding incidental applications for neglected diseases, government and philanthropic funders have also invested in product development partnerships. Sharing knowledge requires an enabling environment. The investment required to transfer information is a measure of the “stickiness” of that informa - tion.14 Stickiness is a function of the attributes of the information itself as well as that of the information seekers and providers. Intellectual property rights might make such knowledge costly to acquire while information technology has changed the speed and marginal cost of disseminating knowledge. Sometimes the skills are local to where that knowledge is being used. For example, laboratory apprenticeships may afford the firsthand experience necessary for performing certain procedures. Several factors affect the sharing of knowledge: (1) the nature of the knowl- edge to be shared; (2) the norms for scientific exchange; and (3) its role in the innovation process. Today’s science has many ways of codifying knowledge, from study methods described in journal articles to patents disclosed. Tacit knowledge,

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 APPENDIX F on the other hand, is not well codified. A technology new to developing country firms—such as conjugation technology for vaccine production—may not easily transfer without technical assistance. Norms over the ownership of knowledge also influence the sharing of knowledge. These norms are rooted in statutes and regulations such as the Bayh-Dole Act, prevailing practices among research institutions, and guidance provided by funding agencies as well as competition among scientists. The sharing of knowledge matters most if innovation and scientific progress are cumulative. By cumulative innovation, one might envision several types of arrangements of research inputs and outputs (see Figure F-1).15 A single innovation might spawn multiple, second-generation innovations. For example, a receptor target might lead to several promising new drugs. Alternatively a second-generation output might require the input of multiple first-generation inputs. Some of these inputs may eventually be incorporated into the second- generation product, but other needed inputs—research tools—will not be. Finally, the process of innovation may be a quality ladder, where successively better products build on the model of the previous one. Process innovations of drugs can lower the marginal cost of production, extend its shelf life outside the cold chain, or improve its bioavailability. Each pattern of cumulative innovation responds differently to the ways in which knowledge is shared or inventions are licensed. For example, a product patent on a drug effectively may block others who might otherwise pursue process innovations in the manufacture of that drug. Those who benefit from this sharing of knowledge must have the absorptive capacity to apply and sustain its use. The transfer of technology depends on the absorptive capacity of the setting where it would be used. Technology has both hardware and software aspects. Hardware is the tool as embodied as a physical object while software is the information base for the tool.16 The capital costs for purchasing hardware may be out of reach, but so might be the maintenance costs. Variable costs such as reagents for diagnostic tests can be prohibitively expensive. The software side consists not just of the knowledge to use the tool, but also may require the human resource expertise to apply it. ACCESS TO THE BUILDING BLOCKS FOR RESEARCH From bench to bedside, the value chain of R&D consists of inputs and out - puts at every stage, each dependent on the sharing of knowledge. Three stages in this value chain warrant closer scrutiny because decisions at these points signifi - cantly shape what knowledge is shared within the scientific community. These building blocks for research include access to scientific publications, the norms for data and material sharing, and patenting and licensing practices. Character- izing the obstacles and opportunities at each stage can help point the way to solu - tion paths that lower the barriers to sharing knowledge and improve the scientific community’s ability to respond to the challenges of global health.

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 THE U.S. COMMITMENT TO GLOBAL HEALTH Cumulative Innovation Generation 1 Generation 2 A) Tiering Pooling B) C) FIGURE F-1 A) Innovation may occur in several ways. One input may lead to a higher quality output, with each generation of F-1.eps bringing a successively better product. innovation Alternatively, a single input may spawn several outputs, as one target receptor may lead to several new drugs. Finally, several inputs may be required to produce one output; these inputs may be innovations themselves or simply research tools (adapted from Scotchmer, 2004).15 B) Tiering may segment the marketplace between a paying market and a resource-limited one that may receive a discounted price or other preferential access. C) Inputs may also be pooled, thereby reducing transaction costs to innovation and more readily enabling socially useful bundles. Such pooling—particularly when strategically done by the public and/or philanthropic sectors—may be structured to influence positively the norms and the licensing by which other inputs are also made available for innovation. Such an arrangement characterizes a technology trust. Access to Scientific Publications The challenges to sharing knowledge through scientific publication come both from the supply and the demand side. On the supply side, studies suggest that industry funding may not only occasionally introduce potential bias into the conduct of research, but also possible delays in its publication. Of those respond - ing to a survey of life science faculties at universities receiving the most NIH

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 APPENDIX F funding, nearly a third of the investigators that benefited from corporate research- related gifts indicated that their industry sponsor wanted pre-publication review of journal articles resulting from the gift.17 A majority of the contracts struck between these scientists and life science companies also mandated a six-month period of confidentiality to give time for patenting of resulting inventions.18 By contrast, the NIH has provided guidance that such delays should not exceed a 30- to 60-day window. On the demand side, subscription prices to journals may place access to some research out of reach. This problem not only faces some institutions in the developing world, but also among patients in the developed world. For many patients, especially those with rare diseases, the high cost of accessing individual journal articles can pose an obstacle to learning about one’s condition or treat - ment options. As a result, patient advocacy groups have recently joined the call on the U.S. government to embrace open access policies.19,20 To ensure greater access to scientific publications, several strategies have been deployed. One has involved tiered pricing, and the other, the pooling of pub- lished research in open-access journals or repositories. Particularly in developing countries, mailing hard copies of journals would be prohibitively costly. With the advent of the Internet, however, much of this access can now be provided electronically. Launched in January 2002, the WHO-led Health InterNetwork Access to Research Initiative (HINARI) seeks to provide tiered access to more than 6,200 major journals in biomedicine and related social sciences. In collaboration with participating publishers, HINARI divides low- and middle-income countries into two groups: countries with a GNI per capita from US$1250-3500/year whose institutions can receive access for $1000/year and those below that cutpoint whose institutions receive free access via an online research portal.21 The pub- lishing company Elsevier, whose journals are made available through HINARI, claimed in 2006 that the initiative contributed to raising the rates of publication by researchers in the 105 HINARI-eligible countries. In their analysis, research - ers in HINARI countries increased their rates of publication by 63% while those in non-HINARI nations saw only a 38% increase.22 However, some problems have surfaced in gaining online access to these journals. In order to be eligible for HINARI access, researchers in developing nations must have an institutional affiliation, prohibiting nonaffiliated scientists, doctors, and government officials from accessing HINARI articles.23 Even for those with the correct institutional affiliation, investigators from a Peruvian university noted in 2007 that many of the highest impact journals were not available there.24 Those journals that were accessible via HINARI were often either open-access journals or those which already provided free access to low-income countries. Across disciplines ranging from electrical engineering to mathematics, the free, online access of journal articles corresponded to higher mean citation rates. 25 Several studies suggest that open access articles have a higher citation rate than

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 THE U.S. COMMITMENT TO GLOBAL HEALTH closed-access articles.26,27 This held true even when comparing open-access articles compared to non-open-access articles in the same journal.28 Importantly, the impact of open-access publication on citations in journal publications was twice as strong in the developing world.29 Open access can take several forms. By retaining copyright or nonexclusive license, authors can self-archive their work, oftentimes on their own websites or in a university repository. This is also known as the “green” road. In early 2008, Harvard University adopted its own open-access mandate through which members of the Faculty of Arts and Sciences will submit electronic copies of all completed articles to an institutional repository that will eventually be accessible worldwide via the Internet.30 Faculty members may opt out of the system if they choose, but it is expected that most will grant a nonexclusive license to the uni - versity to make use of their work. The approach of an institutional open-access repository has also spread: Harvard Law School and Harvard’s Kennedy School of Government recently adopted their own open-access initiatives as have the Stanford University School of Education, Boston University, and the Massachu- setts Institute of Technology.31,32,33,34 Breaking with the approach to supporting journal access through subscrip - tions, open-access journals have offered an alternative model to scientific pub - lishing, also known as the “gold” road. Open-access journals raise revenues from a variety of sources—endowments, institutional subsidies, membership dues, fundraising, advertising, or upfront submission or publication fees—or just depend on voluntarism. Of note, most open-access journals do not charge any publication fees.35 Open-access journals make published articles more broadly available online without subscriber fees. In so doing, open-access journals enable wider distribution of the research published in these outlets, and at the same time, the copyright licensing of these works allow greater potential of “remix.” For example, if a developing country research institution sought to pull together a compendium of key articles on schistosomiasis and to share such a resource with sister institutions, the transaction costs of assembling an open-access collection of journal articles are far lower than doing so with non-open-access articles, where reprint rights would have to be negotiated with each journal holding the copyright. Open-access publishing has benefited from Creative Commons licensing. Such licensing enables artists, writers, and researchers to lift voluntarily some or all of the copyright restrictions upon their work. The family of Creative Com- mons licenses allows for different permutations of the conditions under which the work might be distributed, displayed, performed, or become the basis of a derivative work. These conditions may require attribution, limit subsequent use to noncommercial purposes, not allow derivative works, or allow sharing under condition that derivative works carry the same licensing. In the biomedical sciences, much research is funded by governments, and given this support, the public understandably expects access to the findings

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 APPENDIX F from such research. The NIH estimates that 80,000 publications grew out of NIH-supported research in 2003.36 Initially making a nonbinding request of its researchers, NIH asked that all publications resulting, in whole or in part, from its funding to be deposited in PubMed Central, a publicly accessible archive of scientific publications, within 12 months after the study’s publication.37 How- ever, the yield from voluntary compliance with this policy was very low: fewer than 5% of NIH-funded researchers submitted their articles.38 The failure of this policy prompted U.S. congressional action that mandated it as a requirement of NIH funding beginning in April 2008.39 The NIH Public Access Policy requires investigators to submit final, peer-reviewed journal manuscripts arising from NIH funding to PubMed Central upon acceptance for publication. Such papers must be available to the public through PubMed Central no later than 12 months after publication. Taking a green path, this approach mandates deposit of government funded research in an online archive broadly available to the public. By allowing grantees to use NIH funding for publication fees though, the NIH also supports, in part, the gold road. Several prominent medical research funders have made open access a condi - tion of grant support. The European Research Council (ERC), a funding body set up by the European Union (EU) to promote research in the region, has also put forward an open-access policy requiring its grantees to post all publications to a research repository within six months of publication.40 This marked the first EU-wide open-access policy and ERC has stated that it has interest in shorten - ing the six-month window period in the future.41,42 The Wellcome Trust requires submission of scientific publications resulting from its grants into U.K. PubMed Central within six months of the publication date and even provides funding for the upfront fees associated with publishing in such outlets. 43,44 Grantees of the Howard Hughes Medical Institute also face a similar requirement to deposit publications in PubMed within six months of the publication date. 45 By contrast, NIH’s Public Access Policy remains at 12 months, twice the embargo period accepted by other leading funding agencies. Access to Research Data and Materials The sharing of research data and materials enables the scientific community to confirm study findings and also to build upon the work of others. Access to these building blocks of research, however, may also be encumbered for reasons similar to those encountered over scientific publications. The difference is that access to data and materials enriches immensely the pursuit of new hypotheses that derive or go substantially beyond its original research use. Competing public policy concerns set some limits on the sharing of research data and materials. For example, some data may risk the personal privacy of human subjects, and the disclosure of other data may compromise the confiden - tiality of privileged proprietary information. Unlike the electronic distribution of

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 THE U.S. COMMITMENT TO GLOBAL HEALTH journal articles or data, the marginal cost of disseminating research materials may not be negligible, and these transaction costs also may pose barriers to sharing. Dual use of technologies have the potential both to advance scientific knowl - edge and to pose threats to public health or the environment, and such research activities as well as resulting data and materials require governmental oversight. 46 However, denying data access not only imposes additional costs and barriers to research along these lines, but also can place patients at risk of redundant or unnecessary clinical trials. Slow responses to material transfer requests resulted in project delays of greater than a month among one out of six biomedical researchers surveyed in universities, government or nonprofit institutions.47 Noncompliance with these material transfer requests resulted in 1 out of 14 scientists giving up a line of research on at least one of their projects each year. While noncompliance with these requests were not reported to relate to the patent status of the requested material, key reasons given for noncompliance included the costs and effort involved in providing the sample and protecting the ability to publish. Negotiating MTAs with industry often came with conditions, such as reach-through claims, royalties, and publication restrictions. This was particularly common for requests for drugs. The role of government in facilitating access to data and research materials is bounded, in part, by statute and regulations. For example, the U.S. Copyright Act of 1976 prevents the federal government from claiming copyright protection of its publications, and OMB Circular A-130 mandates that government-produced data should be made available at the marginal cost of disseminating it. OMB Cir- cular A-76 prohibits the government from entering into direct competition with the private sector in providing information products and services. Tensions exist between treating scientific data as a public good as opposed to a private one, and there are important implications for the research commons.48 As with publications, open access may also multiply the impact of research data. For example, in a 2007 study of 85 cancer microarray clinical trial publica - tions, the public sharing of available data contributed to a 69% increase in cita - tions.49 While half the trials in the study made their data publicly available, they comprised 85% of the total citations. As suggested by findings in the genetics research community, there are the familiar reasons for denying access to data and research materials. When making requests for information, data, or materials related to published research, nearly half of geneticists reported that at least one of their requests had been declined over the previous three years.50 Consequently, investigators said they could not confirm research that had been published. Among the reasons most frequently given for denying such requests, geneticists cited the high costs of producing materials or information, the need to protect their own or their colleagues’ ability to publish, and the commercial value of the data or material. In the setting of emerging infectious diseases, the need for rapid and freer

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 APPENDIX F exchange of information and materials has become most clearly evident. The WHO’s Global Influenza Surveillance Network played a key role in linking the world’s leading laboratories and experts with real-time information during the SARS outbreak in 2003.51 In the race to identify the coronavirus as the cause of SARS, 11 laboratories recruited by the WHO regularly and voluntarily shared samples of the unknown virus and held conference calls to discuss their results. 52 Without this level of collaboration and sharing, the transmission of SARS might not have been halted within four months. For other diseases that might not unfold as infectious disease outbreaks, would not freer exchange norms also help speed the race to a cure? Funding agencies again have played an important role in setting norms for sharing data and materials. Providing guidance to its grantees in 2003, the NIH requires applicants for grants greater than $500,000 to provide a plan for “timely release and sharing of final research data from NIH-supported studies for use by other researchers.”53 The ERC requires that “primary data” such as nucleotide or protein sequences or epidemiological data must be submitted to a database within six months.54 Led by the Wellcome Trust and the NIH, leading sequence centers involved in the Human Genome Project pledged to deposit completed gene sequences of every 1,000 base pairs within 24 hours of completion into a publicly available database, GenBank. Called the “Bermuda Rules,” these rules were created to pre- vent the patenting of DNA sequences through defensive publishing.55 Providing further incentive to follow the Bermuda Rules, the NIH subsequently suggested that the patenting of work emerging from the publicly funded Human Genome Project would negatively impact the likelihood of receiving future grants.56 Data sharing has also been supported by other initiatives since the adoption of the Bermuda Rules—by the Merck Gene Index,57 the International Nucleo- tide Sequence Database Collaboration,58 and the Worldwide Protein Data Bank among others.59 Traditionally, the sharing of data and materials involves both informal and formal norms. Informally researchers sometimes bypass negotiation over mate- rial transfer agreements (MTAs), but such practices may place the institution at some risks that would otherwise be lessened by use of MTAs. Informal transfers of materials among investigators circumvent institutional management of the intellectual property and give advantage to some researchers better connected than others.60 Increasingly though, informal sharing has given way to formal agreements on data or material sharing that cover concerns such as attribution, protection of patient confidentiality, the right to publish resulting research find - ings, and intellectual property rights (IPRs). Various groups have sought to lower the costs of such transactions. The first strategy involves harmonizing the formal agreement form used among institu - tions. The Uniform Biological Material Transfer Agreement (UBMTA) offers a standard approach for transferring materials for noncommercial, research pur-

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 THE U.S. COMMITMENT TO GLOBAL HEALTH In the region, countries range from large middle-income country markets like Brazil to smaller, least developed country markets like Haiti. Tiered pricing avail- able to Haiti may not be so for Brazil. Under the Accelerating Access Initiative, five pharmaceutical manufacturers offered lower prices for HIV medicines by brokering agreements on a drug-by-drug, country-by-country basis. With only five countries in Latin America and the Caribbean initially participating in this Initiative, the countries of the Caribbean started a subregional negotiation with Accelerating Access Initiative partners. Central American countries soon fol - lowed suit en bloc, and then ten other Latin American countries started collective negotiations.107 Each subregional negotiation improved upon the country-by- country negotiations with the Accelerating Access Initiative. The important les - son from this experience is the monopsony power of collective negotiation—or pooling—for tiered pricing. Apart from organizing demand, pooling can facilitate access to the supply side by constructing a research commons. Such a step can lower the transaction costs of assembling these research inputs. Pools can come together by various means. Upstream in the R&D pipeline, pooling can build upon a more robust public domain of research tools and other inputs. The entanglements of IPRs might be fewer over the building blocks of knowledge. Downstream in the R&D pipeline, commercializable inventions will play a more important role in the pool, so the mix of incentives to contribute and disincentives to leave the pool may be more complicated to structure than in upstream pools. By applying the Creative Commons Attribution License, open access publi - cations create pools of journal articles that permit “unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.” Open-access repositories for data and journal articles posted online at universities similarly pool research resources for broad, public availability. Norm- setting approaches like the adoption of the UBMTA have the same potential, but when universities substitute their own more restrictive MTAs in lieu of following the UBMTA, the fragility of such pooling arrangements becomes clear. While private sector pools provide access to patents comprising MPEG-2, DVD and other standards in the electronics industry, the creation of pools in biomedicine has been slower in coming. There certainly have been fledgling efforts to create a SARS patent pool,108 to develop UNITAID’s proposed patent pool for HIV/AIDS drug products,109 and to seed a technology trust for neglected diseases.110 Recently though, GlaxoSmithKline stirred renewed interest in this approach with its announced commitment to donate more than 800 patents to a pool open to researchers working on developing treatments for neglected dis- eases.111 Going beyond patent pools, the “technology trust” model explores the potential for pooling across the value chain, from open-access databases to pool - ing of patented inventions. Using various arrangements for collectively managing intellectual property, it emphasizes the normative role that public sector pooling and its strategic use of IPRs can play in encouraging greater scientific exchange and innovation.112

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 APPENDIX F Significant start-up costs exist for creating a pool. Organizers have to con - sider how to define what patents are essential to a pool or not; set valuation and remuneration, if any, for patented inventions or copyrighted materials in the pool; establish incentives for joining the pool and disincentives for leaving it; and seek antitrust guidance to ensure the pool is pro-competitive. In agricultural biotech - nology, the Rockefeller and McKnight Foundations along with 10 universities created Public Sector Intellectual Property Resources in Agriculture (PIPRA) in 2003. Its stated goals were to “overcome the fragmentation of public-sector IP rights and re-establish the necessary FTO [freedom to operate] in agricultural biotechnology for the public good, while at the same time improving private- sector interactions by more efficiently identifying collective commercial licensing opportunities.”113 Acting more as a clearinghouse than a pool, its public database comprised of patented inventions from member institutions makes it easier to identify socially useful bundles of intellectual property for commercialization. Public sector and philanthropic funders seldom foot these transaction costs for pooling in biomedical R&D. NIH grantees cannot charge legal fees for pat - enting or licensing as a direct cost to their project. However, it can be built into the indirect facilities and administrative costs of a grant. This certainly limits the means by which nonprofit research institutions might be willing to use IP strategi- cally to protect the public domain. After all, patenting involves both legal, filing and maintenance fees, and protecting IP for the public domain does not promise a financial return on this investment. Nonetheless, the willingness of some funders and even some universities to support upfront fees for publication in open-access journals is a promising step in this direction, perhaps one that might be emulated when patenting to protect public access is at stake.114,115 Not paying these transaction costs for pooling, however, can be problematic, particularly for emerging infectious diseases. In these cases, the spread of the epidemic may outpace the prosecution of patents at the Patent Office. As a result, developers of diagnostics and treatments for the disease receive little certainty from the patent system as the epidemic unfolds. The U.S. Centers for Disease Control and Prevention and the British Columbia Cancer Agency argued that the rationale for rushing to the Patent Office during the SARS outbreak was to maintain the freedom to operate for potential innovators in this space. 116 This example reveals the perceived need by public agencies to patent in order to pro - tect researcher access and the public’s interest in areas of critical public health concern. With patents still issuing years after the initial SARS epidemic has been contained, pooling may help resolve the uncertainty faced by pharmaceutical firms working on emerging infectious diseases during the outbreak. Effectively used, tiering and pooling efforts can contribute to greater open - ness in the sharing of knowledge. Open-source science focuses more on the way in which the resulting collaboration is organized. Taking a page from the free software movement, the philosophy is embodied in the General Public License that allows a copyright owner to license a user to use his or her work, examine the underlying source code, modify it, and redistribute modified or unmodified

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 THE U.S. COMMITMENT TO GLOBAL HEALTH versions of the work. The license provides this right without paying a fee in return to the owner, but stipulates that the same conditions must be passed along to any subsequent user of that work. This open-source approach turns the traditional model of innovation on its head. Open-source production empowers end users in the innovation of a technol- ogy, and in so doing, emphasizes transparency as well as peer review and feed- back.117 Attribution of contributions in such communities is more difficult to trace than the authorship of scientific publications. With the successful experiences of open source in software, would such an approach apply in biomedicine? Perhaps bioinformatics might be, by analogy, a good starting point. The advent of the Internet has certainly changed the costs of open-source production. Distributed computing projects such as Folding@Home involve nonscientists and scientists alike in contributing desktop computing power to solving computationally inten - sive problems like protein folding. Moving from distributing computing projects to peer-based production among scientists may be more challenging. Still some have applied similar open-source principles to biomedical science. Initially the Haplotype Map (HapMap) Project required users of its database to agree to a license, whereby investigators committed “not to use the data in any way that will restrict the access of others, and will only share the data obtained with others who have accepted the same license.”118 While such a license reaches virally through to subsequent users of the data, it may pose problems for those seeking to commercialize inventions in a marketplace where secure IP holdings can spell the difference between access to venture capital or not. Some have proposed the possible application of open source to finding cures for tropical diseases, where there is not a large paying market.119 The adoption of such an approach among wet lab scientists has been slower in coming. However, the Open Source Drug Discovery (OSDD) project, launched by India’s Council of Scientific and Industrial Research in 2008, is a promising model to watch. The online platform allows a community of scientists to share and collaborate on projects, from gene sequencing to new drug development, on Mycobacterium tuberculosis. Backed by US$38 million in commitments from the Indian government, this open-source website has already engaged 700 par- ticipants from 130 cities across 56 active projects.120 OSDD differs from previ- ous open-source drug discovery projects in that it has the support of a leading research institution in a major developing country, promises to adopt 30 colleges throughout India where students will have the opportunity to contribute research to this initiative, and importantly, has substantial financial resources to leverage research collaborations. Public financing may be the key to applying open-source production in biomedicine, both paying for what cannot be volunteered and sup - porting the open exchange important for collaboration. By reengineering the value chain of R&D, alternative models for innovation may emerge and potentially better meet the needs of global public health. The approaches of tiering, pooling, and open source point to potential ways in which

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 APPENDIX F the sharing of knowledge might be improved. While some of these efforts will emerge spontaneously from the scientific community, others will require targeted and strategic public and philanthropic investment. Unlike the private sector, the public and philanthropic sector does relatively little to manage collectively or strategically its IPRs to seek fair returns from its investment. Yet arguably if publicly funded research were not freely available, the tax- payers would have paid for the results several times over—grants for the aca - demic research, salaries for those academics giving their time for peer review, and subscriptions for such journals.121 For drugs, diagnostics, and vaccines, taxpayers pay for much of the basic science and some of the clinical research, the academic training of research scientists, and of course, for the final product. Some have argued for the federal government to pay for clinical trials, so that the results would be treated as a public good.122 This calculus of “pay now or pay more later” might guide where the public ought to direct its investments to maximize the returns to the health care system. For example, in the value chain of scientific journal publication, paying the pub - lication fees for open-access journals is one way of supporting a business model that encourages the sharing of knowledge. Going further, the U.S. government could develop a system of supporting open-access journals that publish peer- reviewed, publicly funded research. For those open-access journals that charge publication fees, it could build support into the direct or indirect cost structure of grants. For those open-access journals that do not charge fees, it could provide direct or indirect subsidies. Either way, it could support journals that provide open access rather than impose subscription fees on patients, providers, and universi - ties. This support could factor in transition costs, the citation impact factor of the journal in that field, the rejection rate, and the number of publicly funded research articles published by the journal. For clinical trials, greater public funding could also reap significant benefits. If structured appropriately, such support might result in improved data transpar- ency and access, the sharing of clinical trial information on shelved products, the removal of financial conflict of interest in the conduct of clinical trials, priority placed on trials addressing major public health concerns, and transparency of R&D costs that might allow policy makers to assess reasonable pricing of the resulting products. The recently approved NIH funding for comparative effective- ness trials is a useful first step in this direction.123 Reengineering the value chain might also involve investing in alternative business models, one that might lower the cost of R&D for neglected diseases. The Gates Foundation grant to the Institute for One World Health, the University of California, Berkeley, and Amyris Biotechnologies to produce artemisinin at no profit for the developing world is one such example. Another example comes from the work of Global Vaccines, Inc., a nonprofit firm that seeks to develop affordable products for developing country markets with the support of public funding and then to disseminate this technology through commercial sublicenses

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0 THE U.S. COMMITMENT TO GLOBAL HEALTH for markets in industrialized countries. With Wellcome Trust and UK govern - ment funding, investigators from Imperial College and the London School of Pharmacy reengineered not only the existing version of hepatitis C treatment, pegylated interferon, but also the approach to help ensure its scale-up as a product affordable to the many afflicted with this disease in the developing world.124,125 Through a university spin-off, they licensed the drug to Shantha Biotechnics, bypassing the more customary route of licensing it to a multinational pharma - ceutical firm. Facing different clinical trial costs, Shantha Biotechnics will try to produce a more affordable treatment than the one currently available. Sharing knowledge from bench to bedside is critical to bringing about inno - vation the world—and particularly its poor—need from the biomedical sec - tor. Overcoming the disparities between industrialized and developing countries sometimes seems like a Sisyphean challenge, but strategic steps taken by the public and philanthropic sector can help create an environment that enables both North and South to work together towards improved innovation and greater access to health technologies. ACKNOWLEDGMENTS The authors gratefully acknowledge the support of the Institute of Medi - cine and a grant from the National Human Genome Research Institute (Grant 5R01HG003763, Building a Technology Trust in Genomics) as well as insightful feedback from Sarah Scheening on the IOM Program staff, the IOM Committee, and several experts, including Professor Peter Suber, Professor Arti Rai, Shaoyu Chang, MD, MPH, and Joseph S. Ross, MD, MHS. ENDNOTES 1 UNESCO (United Nations Educational, Scientific and Cultural Organization). 2005. UNESCO Sci- ence Report 00. Paris, France: UNESCO. Available at: http://www.unesco.org/science/psd/ publications/sc_rp_05.shtml. 2 Glickman, S.W., J.G. McHutchison, E.D. Peterson, C.B. Cairns, R.A. Harrington, R.M. Califf, and K.A. Schulman. 2009. Ethical and Scientific Implications of the Globalization of Clinical Research. N Engl J Med 360(8): 816-823. 3 Michael R. Reich, editor. 1998. International strategies for tropical disease treatments: Experi - ences with praziquantel. Geneva, Switzerland: World Health Organization, Action Programme on Essential Drugs, Division of Control of Tropical Diseases. Available at: http://apps.who. int/medicinedocs/collect/medicinedocs/pdf/whozip48e/whozip48e.pdf. 4 WIPO (World Intellectual Property Organization). 2008. World Patent Report: A Statistical Review. Geneva, Switzerland: WIPO. Available at: http://www.wipo.int/export/sites/www/ipstats/en/ statistics/patents/pdf/wipo_pub_931.pdf. 5 Glickman, S.W., J.G. McHutchison, E.D. Peterson, C.B. Cairns, R.A. Harrington, R.M. Califf, and K.A. Schulman. 2009. Ethical and Scientific Implications of the Globalization of Clinical Research. N Engl J Med 360(8): 816-823. 6 INDEPTH Sites. 2009. Available at: http://www.indepth-network.org/index.php?option=com_ content&task=view&id=50&Itemid=136.

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