PERSPECTIVE ruses with potential. Seasonal influenza viruses are excluded, as are noninfluenza patho- gens irrespective of their pandemic potential. In a globalized world, with myriad emerging infec- Virus sharing, genetic sequencing, tions, the framework’s narrow scope excludes the vast majority of future threats. The ownership and and security sharing of the Middle East respiratory syndrome

1 1 2 coronavirus (MERS-CoV), for example, has been Lawrence O. Gostin, Alexandra Phelan, Michael A. Stoto, controversial, with Saudi Arabian officials cir- 1,2 3 John D. Kraemer, K. Srinath Reddy cumspectaboutglobalcooperation(4). Countries This Perspective focuses on the future of the Pandemic Influenza Preparedness (PIP) Framework, lack the leverage to withhold pathogens already which was initially established to promote the fair sharing of –related pandemic in wide circulation, such as HIV, because scien- influenza samples between countries.We examine the changes that need to be made to address the tists can acquire samples from multiple sources. growing likelihood that genetic sequence data might be shared instead of physical virus samples, as Gaps in global governance well as the need to expand the PIP framework’sscopeandtoimproveitsfairness. The private sector’s incentive to participate is its he Pandemic Influenza Preparedness (PIP) commercial need for viral samples to develop Framework (1) was a milestone agreement pandemic influenza vaccines. But in May 2013, in promoting international sharing of bio- scientists demonstrated that GSD could be used logical samples to develop vaccines, while to rapidly develop synthetic viruses for product T 5 ensuring that poorer countries would have development ( ). If pharmaceutical researchers access to those vaccines. Now genetic sequenc- no longer require access to biological materials ing data (GSD) can allow scientists to develop to develop products, private sector cooperation synthetic viruses rapidly for product develop- in the framework could decline. ment. Electronic transfer of GSD could enable The PIP Framework defines “biological mate- wider access to researchers to innovate and share rials” as influenza viruses with human pandemic

findings, speeding development of life-saving tech- potential, including extracted RNA and cDNA, on January 31, 2016 nologies in a time-sensitive global emergency. which appears to exclude GSD. Although the frame- But access to GSD may also have major implica- work also defines genetic sequences, the frame- tions for , biosafety, and intellectual work’s sharing and benefits scheme does not property (IP). By rendering physical transfer of explicitlyapplytoGSD.Notingthatsomecoun- viruses antiquated, GSD may also undermine the tries treat the publication of pathogen sequenc- effectiveness of the PIP Framework itself, with ing data as highly sensitive, the PIP Framework disproportionate impacts on poorer countries. left for the future the handling of GSD—which In December 2006, Indonesia challenged the suggests that WHO member states and stake- fairness of the global preparedness system by Fig. 1. By sharing influenza viruses with human holders failed to agree during the negotiations. refusing to share samples of avian influenza A pandemic potential and building financial and The omission of GSD in the PIP Framework’s (H5N1). Concerned that wealthier countries would research partnerships, countries can unite to sharing and benefits scheme is out of step with classic.sciencemag.org gain disproportionate access to vaccines while creat- widen access to vaccines. global preferences for the inclusion of genetic in- ing cost barriers for others, Indonesia invoked formation of global health importance in public sovereign ownership of a virus isolated in its ter- Although it has the potential to be transforma- domain or open access databases, to increase trans- ritory. The claimed that the Conven- tive, the PIP Framework leaves fundamental parency and to advance social justice. The Na- tion on Biological Diversity prevents exploitation gaps in health security and in equity. tional Institutes of Health’s genetic sequencing of its “biological and genetic resources,” includ- database GenBank, for example, offers an anno- ing novel pathogens (2). Indonesia’s decision— Gaps in equity, research, and security tated collection of publicly available DNA se- supported by many low- and middle-income ThedynamicsbehindthePIPFrameworkwere quences, which enables data exchange. Similarly, Downloaded from countries—risked significantly impeding the capac- unusual because Indonesia had something to the Global Initiative on Sharing All Influenza Data ity to monitor and respond to novel influenzas. leverage—virus samples critical to the functioning (GISAID) platform promotes sharing influenza- It took more than 4 years, but the World Health of the global public (Fig. 2). The type virus sequences. Although these sequences Organization (WHO) was able to broker the PIP agreement changed an unfair status quo, where- are publicly accessible, researchers must acknowl- Framework, finalized in May 2011 (Fig. 1). It used by lower-income countries shared viruses, while edge the originating laboratories that contributed a novel strategy to advance global justice by af- relying on ad hoc “charitable” donations of vac- data to the GISAID platform and ensure fair use fording more equitable access to the benefits of cines. For example, during the 2009 influenza (A) of research findings. research. Rather than having com- H1N1 pandemic, vaccine donation pledges often mit to providing a share of their vaccine stock- were not fulfilled until high-income countries had Biosafety and biosecurity piles with lower-income countries in exchange for protected their domestic populations (3). In ex- Biosafetyreferstothemaintenanceofsafecondi- access to biological samples, the PIP Framework change for access to biological materials, the PIP tions in biological research to prevent inadvertent created legally enforceable contractual obligations Framework requires researchers and manufac- escape of hazardous materials that could harm on participating private and academic partners turers to fulfill contractual obligations, such as workers, persons outside the laboratory, or the en- that are involved in the manufacture of vaccines providing an agreed percentage of vaccines, di- vironment. Unlike physical virus sharing, sequenc- to make vaccines available to poorer countries. agnostics, or pharmaceuticals to the WHO stock- ing data are not inherently hazardous, and sharing pile or granting developing countries “fair and information instead of physical samples mitigates 1O’Neill Institute for National and Global Health Law, Georgetown reasonable” or royalty-free licenses to manufac- the risk of inadvertent release of the infectious University Law Center, Washington, DC 20001, USA. ture such products. agent by limiting access to biological agents. 2 Department of Health Systems Administration, Georgetown In addition to potential limitations in light of Biosecurity refers to the precautions taken to University, Washington, DC 20057, USA. 3President, Public Health Foundation of , New Delhi 110070, India. GSD discussed below, the PIP Framework is lim- protect against the spread of harmful biological *Corresponding author. E-mail: [email protected] ited in scope as it applies only to influenza vi- substances. This includes pathogens of dual-use

SCIENCE sciencemag.org 12 SEPTEMBER 2014 • VOL 345 ISSUE 6202 1295

likely fall under the scope of “naturally occurring incorporated into existing databases such as the substances” and thus not be patentable as defined GISAID platform. Moreover, allowing free ex- by the World Intellectual Property Organization change of GSD without enforcing the obligations (8). GSD, however, entail additional intellectual owed to the donating country essentially unravels steps from simply isolating the virus. Still, it is the PIP Framework “bargain” after the fact, un- conceivable that GSD might be deemed a non- dermining both the framework’s legitimacy and the patentable “naturally occurring substance” in WHO’s credibility to negotiate future agreements. major jurisdictions such as the (9). In the long run, the gaps in the framework that Although the PIP Framework does not dis- we describe open an opportunity to resolve other place the IP regimes of domestic jurisdictions, existing weaknesses by revising the text. A revised extending the framework to cover GSD would framework should be driven by norms of equity contractually prohibit unauthorized assertions and shared global vulnerability, with the vital goals of property rights over GSD, similar to biological of open access to research materials, accessible materials. Such an expansion of coverage would license agreements, and more rapid development further the framework’s objectives of social jus- of therapeutic countermeasures. Note that fairness tice, while encouraging open access to GSD. requires that lifesaving vaccines and pharma- ceuticals, as well as the results of research, are Global health governance equitably distributed in low- and middle-income Fig. 2. Bird flu in Indonesia: freewheeling toward The private sector (e.g., pharmaceuticals, for- countries that lack the ability to purchase products a pandemic. Biological samples (poultry and pigs) profit providers, food, alcohol, and in the market or produce them domestically. for the detection of H5N1 virus at the Virology tobacco) has powerful effects on the public’s Further, the sharing of biological materials, as Laboratory Control Center for Tropical , health, security, and safety. Yet, the WHO finds well as GSD, should be extended beyond influenza University of Surabaya, Java. [CORBIS] it hard to govern these and other nonstate ac- to all other hazardous pathogens with pandemic tors. When it does mobilize multiple stakeholders, potential, such as novel coronaviruses. If the in- research of concern: life sciences research intended the norms set are usually voluntary, such as through tent of the framework is to facilitate research and for benefit, but which could be misapplied to do action plans or codes of practice. A perennial speed the development of vaccines and antiviral harm, such as through . GSD pose weakness of international agreements is their medications, a narrow scope of application dimin- unique biosecurity threats because of their potential inability to assure compliance. The PIP Frame- ishes the effectiveness of global health governance for broad global dissemination, which results in work not only includes the private sector in global (11). The use of GSD in product development could insecure laboratories or potential terrorists gaining health negotiations but also creatively applies civil prove to be a remarkable achievement. However, access. At present, the technical sophistication to contract law to enforce the agreement—amodel this and other scientific advancements need to be use genetic sequencing to create a hazardous agent for future global health diplomacy. harnessed to safeguard populations worldwide is beyond the expertise of most scientists, and Thus, despite its weaknesses and omissions, the not simply countries that can afford the products presumably more so of potential bioterrorists. PIP Framework offers an innovative template for derived from innovative research. Global health However, the future risk of recreating a lethal virus future global health agreements. The framework securityisvitalbutso,too,isequitableaccess.Not cannot be discounted, especially as sequencing brought together the WHO secretariat, member only will this ensure a more secure and healthy data become more widely available on the Internet states, and the in an un- world, but also a more just world, for humanity. and through scientific publications (6). precedented way. Traditional international law Governments could also use export controls to creates obligations, but rarely, if ever, binds REFERENCES AND NOTES limit sharing of biological materials or GSD. the private sector. The PIP Framework—which is 1. WHO, Pandemic Influenza Preparedness Framework for the — sharing of influenza viruses and access to vaccines and other Many countries require a license to export par- not in the form of a treaty uniquely creates legally benefits (“PIP Framework”), adopted in “Report by the Open- ticularly dangerous pathogens, although export enforceable contractual obligations on participating Ended Working Group of Member States on Pandemic Influenza licenses are routinely granted for legitimate sci- private and academic partners that manufacture Preparedness: Sharing of influenza viruses and access to vaccines ” entific research. In rare instances, governments vaccines, antivirals, or diagnostics. Consequently, and other benefits (WHO Doc A64/8, WHO, Geneva, 2011). 2. E. R. Sedyaningsih, S. Isfandari, T. Soendoro, S. F. Supari, have used export controls to limit dissemination as a method of global health governance, the frame- Ann. Acad. Med Singapore 37, 482–487 (2008). of pathogen GSD—as when the Netherlands re- work has the potential to be transformative. 3. D. P. Fidler, PLOS Med. 7, e1000247 (2010). stricted publication of enhanced H5N1 influenza 4. D. P. Fidler, Foreign Aff., 7 June 2013; www.foreignaffairs.com/articles/ — Filling the gaps in the PIP framework 139443/david-p-fidler/who-owns-mers. research but this is uncommon for unclassified 5. P. R. Dormitzer et al., Sci. Transl. Med. 5, 85ra68 (2013). basic science research (7). A recent WHO review of the PIP Framework 6. J. D. Kraemer, L. O. Gostin, Science 335, 1047–1049 (2012). offered an opportunity to close major gaps but 7. M. Enserink, Science Insider, 25 September 2013; Intellectual property ’ http://news.sciencemag.org/health/2013/09/flu-researcher- also revealed the text s rigidity in adapting to ron-fouchier-loses-legal-fight-over-h5n1-studies. Claiming IP rights is highly polarizing because rapid scientific progress (10). GSD fundamen- 8. World Intellectual Property Organization, “Working paper: it can make essential medicines and vaccines less tally change the paradigm within which the Patent issues related to influenza viruses and their genes” affordable. To ensure greater fairness, the PIP PIP Framework operates, potentially render- (WIPO, Geneva, 2007); www.wipo.int/export/sites/www/ policy/en/global_health/pdf/influenza.pdf. Framework imposes contractual prohibitions on ing the framework less effective. 9. Association for Molecular Pathology v. Myriad Genetics, IP asserted over biological materials transferred In the short run, it would be best simply to 569 U.S. __ (2013). within the WHO Global Influenza Surveillance interpret the framework to include GSD as bi- 10. Technical Expert Working Group on Genetic Sequence Data, “ and Response System. The framework’sintentis ological materials. Keeping GSD under the um- Final Report of the Technical Expert Working Group (TEWG) on Genetic Sequence Data to the PIP Advisory Group” (WHO, Geneva, to prevent recipients of biological materials from brella of a global agreement would facilitate 2014); www.who.int/influenza/pip/advisory_group/en/. exploiting a global resource for their own finan- tracking sequencing data, while holding users 11. L. O. Gostin, Global Health Law (Harvard Univ. Press, cial benefit. Although a contract between the accountable—facilitating socially productive re- Cambridge, MA, 2014).

WHO and a recipient may not invalidate IP rights search, while limiting harmful use. A tracking ACKNOWLEDGMENTS ’ afforded in the researcher s home country, it system need not be burdensome or restrict the Disclosures: L.O.G. was a member of the WHO Technical Expert could permit a lawsuit for breach of contract. free flow of scientific information. A simple reg- Working Group (TEWG) on Genetic Sequence Data to the PIP Countries have varying laws as to whether nat- istration system that monitors who has down- Advisory Group and is the Director of the WHO Collaborating urally occurring biological samples are patentable. loaded GSD would help ensure that recipients Center on Public Health Law and . A biological sample, such as a virus sample, would abidebyglobalresearchnormsandcouldbe 10.1126/science.1257622

1296 12 SEPTEMBER 2014 • VOL 345 ISSUE 6202 sciencemag.org SCIENCE Virus sharing, genetic sequencing, and global health security Lawrence O. Gostin et al. Science 345, 1295 (2014); DOI: 10.1126/science.1257622

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