Policy ForumGlobal Health

Threats to timely sharing of pathogen sequence data

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Science  26 Oct 2018:
Vol. 362, Issue 6413, pp. 404-406
DOI: 10.1126/science.aau5229

Pathogen genome sequence databases are taking over important functions of physical collections of microbial and viral cultures (biobanks), adding functionalities for worldwide rapid sharing of pathogen genetic resources in support of research and outbreak response (1). But biobanks and databases also have to respect the ownership and rights of the sample and data providers, including the sovereign right of states to decide on the use of their resources [as stated in the Convention on Biological Diversity (CBD) (2)]. Where domestic or international regulation in this regard is absent or unclear, the integrity of databases and biobanks can be threatened by divergent interpretations, potentially leading to perceived violation of globally agreed sovereignty rights. In particular, the impact of the Nagoya Protocol (NP) to the CBD on public health and infectious disease control is highly debated and focused now on whether genetic sequence data (GSD) fall within the scope of the NP, which thus far has concentrated on access to physical samples. With this question on the agenda of the upcoming CBD Conference of the Parties (17 to 29 November) (3), we explore possible adaptations of existing biobank frameworks to support efficient transfer of pathogen genetic resources (PGR) during public health emergencies.

Following the West African Ebola outbreak, the World Health Organization (WHO), in consultation with a broad group of stakeholders, concluded that “sharing relevant information before publication should become the global norm during public health emergencies…including pathogen sequences.” If GSD would fall under the NP, the free sharing of sequences for surveillance and tracking of pathogens and outbreaks could become illegal (4).

Transfer of Genetic Resources

The NP is an internationally binding treaty, adopted in 2010, to regulate access to genetic resources [thus far agreed for biological (physical) samples] and to ensure fair and equitable sharing of benefits arising from their use (5). The NP determines that governments can exercise sovereign rights over resources originating from their territory. To this end, national legislation has to be in place and made transparent, preferably by uploading into the CBD's Access and Benefit-Sharing (ABS) Clearing-House. Before users receive any sample from abroad, the NP requires them to check (i) whether the providing state has signed the NP; (ii) whether a law or regulation is available in the ABS Clearing-House, and if not; (iii) to check with the state's authorities if any national law prohibits the access and transfer of the material. Detailed recording of this procedure and correspondence can prove later due diligence if the necessary permit is not available.

With the NP entered into force in 2014, countries can state specific conditions in which the receiving party has to acquire two types of permissions. First, users must obtain prior informed consent (PIC) from the provider's country government. Second, the monetary and/or in-kind terms and conditions for utilization of the genetic resources [the so-called Mutually Agreed Terms (MAT)] need to be obtained from the provider's country government. Differentiation between commercial and noncommercial use is in the NP and for most countries quite essential when deciding on the type and value of ABS conditions in their MAT. The NP promotes the use of internationally recognized certificates and their uploading into the ABS Clearing-House for everyone to access, but other forms of agreements are possible [e.g., through letters or a contractual material transfer agreement (MTA)].

This responsibility of assuring that any shipment of samples is compliant to the NP by obtaining and transferring acceptable documentation presents a substantial burden of which many in the research and public health community are not well aware. For biobanks, where huge amounts of items are stored for multilateral sharing, using standard NP certificates is probably the most workable way of documenting compliance.

Definition, Implementation

A core term in the NP is the “utilization of genetic resources,” defined as “to conduct research and development (R&D) on the genetic and/or biochemical composition of genetic resources, including through the application of biotechnology” (5). But when specific activities are considered, R&D is in many cases not clear. In addition, the issue of “change of intent” is debated, as it is often hard to clearly differentiate between noncommercial and commercial use. Even when jurisdictions provide guidance and interpretation in this regard (6), uncertainty will remain for curators of international biobanks because interpretation of the NP's scope can differ elsewhere in the world. This leaves biobanks in the dark about the legal status and terms of use of their collections.

Another problem is that implementation of the NP conditions in individual countries' national legal systems is a time-consuming process that has not yet been completed in most countries that ratified the NP, 4 years after it entered into force (7). Inclusion of GSD into the NP could lead to even more uncertainty. Opinions on this seem to be deeply divided, starting with widespread confusion about the definition of “digital sequence information” that is now broadly used by the NP (8).

The combination of partial implementation of the NP, lack of clarity on rules and processes, and differences in interpretation at a national level are foreseeable major hurdles, especially in outbreak situations when the timeliness of access to PGR is of essence. Unless clarity is provided for such matters, the ability to respond to outbreaks that require international data sharing is likely to be severely hampered. These barriers are similar for individual researchers and biobanks, but the practical impact for large collections is more substantial, as due diligence has to be exercised with each sample—and possibly soon, each GSD—by acquiring bilateral agreements and necessary documentation determining what is permitted on the grounds of the specific MAT.

Four Models from Biobanks

We present here four models, differing in the role and responsibility of the biobank in negotiating and processing the NP conditions concerning PIC and MAT. We searched examples of biobanks and biobank networks that admit in their collections multiple pathogens and supply materials to multiple stakeholders in different countries. The main difference between the models is where the burden to negotiate ABS conditions lies: Some biobanks and networks require this responsibility from each person (and institute) depositing the sample; some take up this responsibility themselves, providing services and harmonizing procedures; and some simply provide the offered materials while leaving the responsibility to acquire PIC and MAT to (end)users (see the table and figs. S1 and S2).

The American ATCC and Japanese NITE are models of nationally curated biobanks (see fig. S1). In the ATCC, no provision for the acquisition and transfer of NP conditions is made, because the United States has not signed on to the CBD. Thus, users still have to acquire bilaterally all NP documentation themselves (7, 9). The time-consuming and costly bilateral negotiations with multiple countries at a governmental level is problematic for the rapid availability of PGR necessary in a public health emergency. By contrast, the NITE offers certainty about the NP conditions of the materials through preestablishment of bilateral PIC and MAT agreements with certain Asian countries to facilitate transfers of genetic resources. To our knowledge, this is the only model in which a biobank takes up the NP burden also for commercial use of materials [though only for Japanese stakeholders (10)].

The Asian ACM and European ECCO models consist of a network of multiple national biobanks (see fig. S2). In the ACM, there is no need to negotiate bilaterally PIC and MAT, because each of the 13 governments from the countries in the network entered into a memorandum of understanding (MoU) with the ACM curator. A MoU is, in short, not a strictly legally but rather a politically binding agreement. In this case, individual countries' PIC and MAT conditions are waived and replaced by a simple, standardized set of ABS conditions. The NP burden is in this way facilitated by the network curator and the result is, in principle, rapid sharing of materials for noncommercial use between network partners (11). By contrast, for the ECCO model, the administrative NP burden stays on each depositing party that has to submit the PIC and MAT certificates together with the materials at the beginning. The (network of ) biobanks only control the existence and transfer of the NP certificates. When transferring to other repositories or end users, a model MTA of ECCO must be used, but each time the different MAT of each sample has to be incorporated (12, 13). Two challenges still remain for both network models: (i) defining the line between noncommercial and commercial activities and (ii) how public health activities are interpreted in this regard.

National and regional biobank models for compliance with the Nagoya Protocol conditions

Reduce Barriers for Public Health

The American and European models require, either at the start (ECCO) or at the end (ATCC) of the process, isolate-specific bilateral negotiations with the government of origin, resulting in (i) a time-consuming process and (ii) a collection in which each isolate has different conditions of use. The Japanese NITE and Asian ACM models, although containing facilitated ABS negotiations and standard conditions for noncommercial use of materials, consist of closed networks in which only members benefit from the facilitated channels. The standard MTA for noncommercial use in countries outside the ACM network is, however, notable: After signing an MoU, individual PIC and MAT conditions are waived to allow the use of an agreed standard MTA. This is a legally binding contract, resulting in a multilateral system instead of many bilateral negotiations.

In addition to the above-described models, we highlight two multilateral examples for negotiating ABS conditions, developed to work on a global scale: the Food and Agriculture Organization of the United Nations (FAO) International Treaty on Plant Genetic Resources for Food and Agriculture (ITPGRFA) developed in 2001, before the adoption of the NP, and later recognized under Article 4 of the NP (5); and the WHO Pandemic Influenza Preparedness (PIP) Framework, adopted in 2011.

The ITPGRFA uses a standard MTA that covers commercial and noncommercial use. In this MTA, tailor-made benefit-sharing obligations are imposed on the individual users, as indicated by each providing country, beforehand, in a contract with the centralized administrator or curator (14). Further research is needed to assess whether this model could work efficiently and quickly for pathogens, and at what cost. The PIP Framework, by contrast, applies two different standard MTAs for the different intents (commercial versus noncommercial) of use of influenza samples. An in-kind (vaccine supply) and a monetary donation are agreed with “industry partners” (vaccine, diagnostic, and pharmaceutical manufacturers) to be collected by the WHO from the commercial users (15).

The PIP Framework has been successful but has endured several challenges. Laboratories outside the WHO Global Influenza Surveillance and Response System are considered potential commercial users by default, even if they have a public health mandate. The framework also requires a costly administrative and stewardship system of $6 million per year (15). In light of such costs, and questions about whether other pathogens have the potential commercial value of influenza, developing similar pathogen-specific multilateral frameworks for pathogens other than influenza does not seem like a sustainable option (7).

Another way of approaching the undesired delay of ABS negotiations, especially for access and use of PGR during public health emergencies, is the creation of exemptions for this specific context. There is no clear guidance in the NP for the fast sharing of genetic resources in emergency situations, besides a general call on countries to pay due regard to health-threatening situations, in which they may consider in their domestic regulation the need for expedited ABS provisions [Article 8 of the NP (5)]. The European Union (EU) regulation on compliance with the NP (6) contains a special provision for the sharing of PGR in public health emergencies, including the role of biobanks, as in the ECCO model, as “trusted intermediaries.” The key feature is the exemption from the NP's due diligence conditions for a period of 3 months, for strains that are likely to be the cause of a (possible) public health emergency of international concern. After these 3 months, PIC and MAT have to be negotiated or all the materials that were shared destroyed.

In support of this provision, EU guidance documents mention the need for a fast-track procedure, in which access to PGR may be granted first and PIC and MAT acquired later. As such, formal consent can be given retrospectively based on a tracking system with an attached electronic tag known as the global unique identifier. How this exemption period will actually work and whether it will be good enough remains to be seen. Outbreaks can last for a long time, and on ethical grounds, the development of state-of-the-art diagnostics or pharmaceutical products is not easily stopped or turned back when people are seriously at risk or suffering from diseases. In any case, considering an exemption of PGR to the NP should by no means imply that benefits are withheld; such benefits must be shared at least in the form of nonmonetary collaborations and support to epidemic control and response. Outbreak-related research and countermeasures, such as diagnostics and vaccines, must be accessible to all affected countries not only as a legal obligation, but also as an ethical imperative.

If GSD will come under the scope of the NP, a substantial increase of complex administrative mechanisms will arise, both for the receiving party and the providing countries, as well as intermediaries such as biobanks and databases. Additional to managing the huge volume of data, a diversity of hard-to-resolve dilemmas about definitions and the applicability of PIC and MAT to GSD can be foreseen. These include disputes about the origin of the data due to difficulties in tracking transfers; the legality of use of partial sequences; confusion on the status of results of metagenomics and reverse genetics; ownership issues on incremental innovation; and compliance issues for open science, funders, and editors, requiring GSD to be fully and publicly available (8).

Clarification, Collaboration

With the increasing threat of globally dispersed outbreaks, a global response is of crucial importance; hence, the scattered interpretations and implementations of the NP can seriously affect global health by hampering the timely sharing of essential PGR (8).

We found no single biobank or network model for compliance with the NP that resolves all challenges for biobanks to facilitate access, rapid transfer, and use of genetic resources in all situations and on a global scale. The inclusion of GSD in such models will only increase complexity and legal uncertainty, adding to the already persistent problem of tracking the access and use of materials and isolates. Monitoring and traceability of access, transfer, and use of the enormous, and increasing, volume of data are practically unfeasible (8). Additionally, as the nature and extent of use of GSD are variable, defining benefits from the use of the data can be extremely challenging. The NP was not developed specifically by and for the biomedical field, but for broad biodiversity protection and for fair development, trade, and intellectual property objectives, which are usually addressed in separate disciplines and debated in distinct political institutions. This influences the ability of the NP to address comprehensively biomedical needs and practices, especially during public health emergencies.

For swift outbreak response, the world needs to tackle the challenges of excessive ownership over genetic resources, possibly by transferring due diligence obligations to later stages of product development, alleviating the burden and consequential delay on their use for basic research and public health surveillance and response. Further needs are the implementation of simplified sharing agreements based on standardized, multilateral ABS procedures, harmonizing disparate databases and platforms, and clearly defining which activities fall under the NP's scope, including how “digital sequence information” will be understood and treated, with possible exemptions, at least in cases of public health emergencies. Only then will research laboratories and public health institutes be able to contribute optimally to global collaborations for state-of-the-art diagnostics and swift surveillance and response in public health emergencies.

References and Notes

  1. Secretariat of the Convention on Biological Diversity, The Nagoya Protocol on access to genetic resources and the fair and equitable sharing of benefits arising from their utilization to the convention on biological diversity, Montreal (2011).
  2. Regulation (EU) No 511/2014 of the European Parliament and of the Council of 16 April 2014 on compliance measures for users from the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization in the Union (2014).
  3. ECCO core Material Transfer Agreement for the supply of samples of biological material from public collections (2009).
Acknowledgments: We acknowledge the members of the COMPARE Consortium and the European partner project European Virus Archive goes global (EVAg) for inspiration and support. Funding: This study was done under the framework of the EU COMPARE project. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 643476. Author contributions: All authors participated in developing the article's concept and in the critical revision of the manuscript. C.d.S.R. and G.B.H. conceptualized and produced the table and figures. C.d.S.R. drafted the article text, which was revised and edited by G.B.H. and M.P.K. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work. Competing interests: The authors declare no competing interests. Data and materials availability: All data are available in the main text.
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