Info Service on Health Issues (Mar19/02)
Geneva (TWN): A major effort of the World Health Organization (WHO) on pandemic influenza preparedness faces possible weakening as governments grapple with the handling of “genetic sequence data” of viruses.
The Pandemic Influenza Preparedness (PIP) Framework adopted in 2011 was described as a “bold and innovative tool for pandemic influenza preparedness” in the WHO Expert Review Group report in 2016. The basic premise of this innovation is the principle of placing virus sharing and benefit sharing on an “equal footing” which, according to the Expert Review Group, “remains relevant today”.
However, this famous foundational principle is under threat if WHO Members fail to take appropriate decision with respect to the handling of genetic sequence data, potentially jeopardising pandemic preparedness and response.
The PIP Framework (PIPFw) governs the sharing of H5N1 and other influenza viruses of pandemic potential (also referred to as “PIP biological material” in the Framework document) as well as access to vaccines and sharing of other benefits. Transfers of material are subject to two types of Standard Material Transfer Agreement (SMTA). Transfers of PIP biological material from a National Influenza Centre to other WHO designated laboratories within the WHO Global Influenza Surveillance and Response System (“WHO GISRS”) have to abide by SMTA1.
Transfers of PIP biological materials to entities outside of GISRS (e.g. to industry) are subject to SMTA2. This is a one-time agreement between WHO and non-GISRS entities, for such entities to provide benefit sharing (e.g. vaccine/anti-viral/diagnostics) in the event of a pandemic. In addition, influenza vaccine, pharmaceutical and diagnostic manufacturers have to commit to an annual monetary payment known as “partnership contribution”.
At the core of the issue is whether these components of the PIPFw should also apply to receipt and use of genetic sequence data (GSD), and how the use of GSD should be monitored. GSD is usually generated from sharing of PIP biological material and is included in the PIPFw, but at present, the use of this data only triggers payment of partnership contribution.
A WHO factsheet notes that “[s]urveillance and response to influenza requires state-of-the art technological capacities”, adding that “[n]ew technologies are starting to allow genetic sequence data (GSD) derived from influenza viruses to be used for an expanding range of purposes, including, in some cases substituting for physical samples during pandemic risk assessment and the development of commercial products. With such advances, the implications of current technological developments – as well as those that are in progress and those than can be reasonably anticipated – need to be considered in … the context of PIP Framework”.
The handling of GSD was an unresolved matter, left to further discussions when PIPFw was adopted in 2011. Since then, the topic has been studied and discussed extensively.
In 2016 the Expert Review Group found a dissonance in the way PIPFw treats GSD, arguing that this “dissonance, if not resolved soon, could threaten the relevance of the PIP Framework since the sharing of GSD largely operates outside the virus sharing and benefit sharing rules of the PIP Framework”. It recommended that WHO Members recognize that the definition of PIP biological material includes GSD with the effect that all components of the PIPFw are applicable to such material and should equally apply to receipt and use of GSD.
Following the Expert Review Group report, the 2017 World Health Assembly (WHA) adopted Decision A70(10) that, with regard to GSD, requested the WHO Director-General to conduct a thorough and deliberative analysis of the issues raised, including the implications of pursuing or not pursing possible approaches. The 2018 WHA required the WHO Secretariat to submit its analysis to the 72nd WHA in May 2019.
Hence a key decision point for WHO Members at the upcoming WHA is the handling of GSD in the context of the Framework.
The PIPFw came about following realization of the inequities prevailing in the then Global Influenza Surveillance Network (GISN) which only emphasized virus sharing and was operating in conflict with the Convention on Biological Diversity (CBD). The Convention establishes sovereign rights of a country over its biological resources and that access is subject to prior informed consent of the country providing the resources, with “commercial and other utilization” of such resources triggering fair and equitable benefit sharing on mutually agreed terms with the providing country. Based on the same premise, the Nagoya Protocol elaborates on the access and benefit sharing aspect of the CBD. The CBD has 196 Parties while the Nagoya Protocol has 114 Parties.
The H5N1 outbreak in the South-east Asia region in 2006 revealed the GISN to be a system of winners and losers. Countries would share virus samples with the WHO designated laboratories (mostly based in developed countries) that made up the GISN system. These laboratories would develop a candidate vaccine virus which would be shared with the pharmaceutical industry, often without the consent of the country providing the virus sample. The industry received virus samples for making of vaccine, received government grants and made profits from vaccine sales.
Developed countries entered into advance purchase agreements with the pharmaceutical industry to reserve supplies of vaccines and anti-virals in the event of a pandemic. Industry and several WHO designated laboratories also claimed patents over the parts of the shared biological materials and sequences. Meanwhile countries that freely shared the virus samples (often developing countries) did not have timely access to affordable vaccines and anti-virals or to relevant information about the virus samples shared, while the patent system was used to appropriate the materials and knowledge.
The inequalities and inadequacy of the GISN became glaringly clear with the H1N1 pandemic in 2009, when wealthy countries secured access to vital pharmaceutical supplies through advance purchase agreements, while many other countries, especially in Latin America, lacked access.
The WHO virus sharing mechanism, GISN, was renamed WHO Global Influenza Surveillance and Response System (“WHO GISRS”), with the adoption of the PIPFw in 2011 following four years of contentious negotiations that began in 2007. GISRS is essentially an international network of national laboratories coordinated by WHO which comprises 143 National Influenza Centres (NIC), 6 WHO Collaborating Centres (WHO CCs), 13 WHO H5 Reference Laboratories (H5RL) and 4 Essential Regulatory Laboratories (ERLs). Each of these laboratories is governed by their respective Terms of Reference annexed to the PIPFw.
The scope of the PIPFw is limited to influenza viruses of pandemic potential, excluding seasonal influenza viruses or other non-influenza pathogens. All transfers of PIP biological material among the WHO GISRS laboratories (e.g. from a NIC to WHO CC) are subject to standard terms and conditions governing their use as contained in SMTA1 (Annex 1 of the Framework). SMTA1 requires inter alia the recipient to comply with the Terms of Reference for GISRS laboratories, making clear as well that neither the provider nor the recipient should seek to obtain any intellectual property on the materials.
All transfers of PIP biological material by WHO GISRS to entities outside of the GISRS network (e.g. to pharmaceutical companies) are subject to standard terms in SMTA2 (Annex 2 of the Framework), an agreement between WHO and the entities receiving PIP biological material. It lists different benefit sharing options for different types of recipients e.g. influenza vaccine and antiviral manufacturers, manufacturers of other pandemic-related products, and other recipients. SMTA2 is clear that the recipient shall only further transfer the PIP biological material if the prospective recipient has concluded a SMTA2 with the WHO.
These SMTA2s are in effect a legal commitment by the manufacturers to WHO, as of 2018, to supply more than 400 million doses of pandemic influenza vaccines, 10 million treatment courses of antiviral drugs, 250 000 diagnostic kits, and 25 million syringes in the event of a pandemic. These commitments strengthen WHO’s ability to respond in a timely manner to demands of countries in need during an influenza outbreak of pandemic potential.
The PIPFw also requires annual partnership contributions by influenza vaccine, diagnostic and pharmaceutical manufacturers “using the WHO GISRS”, for a total of USD 28 million (i.e. “50% of the running costs of the WHO GISRS” which were in 2011 estimated to be USD 56.5 million). It is acknowledged that this partnership contribution will change over time. To date, WHO has collected a total of USD 178 million, with 70% being used for national capacity building activities to strengthen preparedness while 30% is maintained for future pandemic response.
An issue that remained unresolved in the PIPFw was the “handling of genetic sequence data” (GSD). GSD is part of the Framework. It states that GSD “should be shared in a rapid, timely and systematic manner with the originating laboratory and among WHO GISRS laboratories”. It also recognizes that access to GSD “is important to public health” and that “in some instances the publication of GSD has been considered sensitive by the country providing the virus”. However, the “handling of genetic sequence data” was an issue left to further decision among WHO Members as the Framework was adopted.
The 2019 WHO Global Influenza Strategy stresses that the “continued implementation and success of the PIP Framework are essential to global pandemic preparedness”. However, its continued success is very much dependent on how WHO Members address the subject of GSD.
New Genetic Sequence Data Technologies
WHO’s 2018 factsheet titled “New technologies using genetic sequence data” points to technological advances where manufacturers use GSD to synthesize biological material for vaccine development. It states that “[a]n increasing number of vaccine manufacturers are using GSD as an alternative to conventional whole virus approaches. That is, manufacturers can – in some cases – now use specialized machines (similar to ink-jet printers) that transform genetic sequence information in digital form into molecules such as DNA, RNA and proteins, or even whole viruses. Those molecules and viruses can then be used in different ways to make vaccines.”
The factsheet highlights GSD (generated from sharing of PIP biological material) can now be used to develop synthetic virus material including candidate vaccine virus without using original influenza virus material. These synthetic candidate vaccine viruses can then be used to develop vaccines through traditional vaccine production methods (e.g. egg-based or cell-based). It also discusses research and development underway on use of GSD with respect to vaccine technologies such as “nucleic acid vaccines” and “universal vaccines”.
As with the PIP biological material, the PIPFw requires the sharing of GSD, and yet GSD and the physical biological materials are dealt with differently under the PIPFw.
Presently the use of GSD does not trigger SMTA1 or SMTA2. Its use only triggers payment of Partnership Contribution. This differentiation has created “gaps and loopholes”, eroding the “equal footing” principle, with the potential to threaten pandemic preparedness.
A major gap is the non-application of SMTA1 to GSD, meaning there are no terms and conditions governing the sharing of GSD. So, for example, can patent claims be made by GISRS laboratories in connection with the GSD?
Similar concerns also arise in relation to SMTA2.
The WHO Secretariat found two fundamental loopholes with regard to manufacturers using GSD wherein SMTA2 is presently not applied. The first loophole is where certain influenza manufacturers developing vaccines with GSD rely on or engage with laboratories having PIP biological material to do testing of the products for marketing, without receiving the physical material per se.
The second loophole is where the development and marketing of influenza pandemic products is solely by using GSD, a reality in the near future as technologies mature. WHO’s general observation on its findings is that “as new influenza manufacturers enter the market, this ‘loophole’ may reduce WHO’s access to certain benefits and potentially jeopardize PIPFw implementation”.
As physical materials become increasingly irrelevant, and reliance on GSD increases, even existing signed SMTA2, may be in jeopardy. As “PIP biological material” is the subject matter of the signed SMTA2, manufacturers may in the future no longer feel obliged to comply with the terms of the agreement. There may also be a scenario where a manufacturer has a signed SMTA2 with WHO under which it has been receiving PIP biological material. However, that manufacturer may terminate its existing SMTA2 with WHO by giving 6 months’ notice, and shift its influenza manufacturing to GSD technologies, without having to commit to a new SMTA2 providing WHO any influenza vaccines, diagnostic and anti-virals developed from use of such GSD during a pandemic. This scenario was confirmed by the WHO Secretariat to be a credible possibility during a recent information session organized by the WHO.
In an attempt to address the subject of GSD, the WHO Secretariat has proposed footnote text in the PIPFw that would extend SMTA2 to “entities that engage with recipients of PIP biological materials for the purpose of supporting development, testing or regulatory processing of an influenza-related product”. The proposed text only resolves one benefit sharing loophole with regard to GSD i.e. where a manufacturer develops an influenza product through use of GSD without receiving PIP biological material, and instead engages with a laboratory that is recipient of such material to conduct testing.
The proposed footnote does not address other major gaps and loopholes discussed above, risks creating inconsistencies in the implementation of the PIPFw, and falls short of what is required to address GSD on an “equal footing”.
“PIP biological material” definition and GSD
Section 4.1 of the PIPFw provides an open-ended and non-exhaustive definition of PIP biological material.
A Technical Expert Working Group (TEWG) established by the PIP Secretariat and the Advisory Group on the subject of GSD noted, “that there are different perspectives on whether genetic sequence data (GSD) are included in the definition of PIP biological material. While at present GSD is not expressly mentioned in the definition of PIP biological materials, the TEWG agreed that GSD falls within the PIPFw (e.g. section 5.2; Annex 4, point 9; Annex 5 ‘Guiding Principles’), and that the spirit of the Framework and the importance of maintaining equal footing for the sharing of viruses and benefits derived therefrom, must be kept in mind in considering issues related to the handling of GSD for H5N1 and other influenza viruses with pandemic potential.”
Maintaining the equal footing principle requires accepting that the PIPFw components should apply to GSD as they apply to PIP biological material. This can be achieved by a simple resolution adopted by WHO Members clarifying that the definition includes GSD and any materials generated from the use of GSD.
WHO Secretariat’s own analysis reveals that maintaining the status
quo creates serious challenges:
(ii) Threaten the “equal footing” principle of the Framework;
(iii) Jeopardize IVPP and IVPP GSD sharing if Member States and stakeholders lose trust in the PIP Framework adding “[a]s noted by the WHO Technical Expert Working Group on GSD, without mechanisms to ensure fair and equitable benefit sharing for IVPP GSD “the attainment of essential objectives of the PIP Framework may be systematically frustrated” […] some countries may be reluctant to share IVPP and IVPP GSD if they perceive the handling of IVPP GSD as inequitable”;
(iv) IVPP GSD could be regulated in a bilateral manner under domestic access and benefit sharing legislation which “could have significant implications for the sharing of IVPP GSD as well as for pandemic influenza preparedness and response. In addition, products developed using both PIP biological material and IVPP GSD could face a complex legal status”.
[Note: GSD and implications for access and benefit sharing are also being discussed in the CBD and the Nagoya Protocol. The Africa Group, the Like-minded Megadiverse Countries, and generally many other developing countries are of the view that it falls within the scope of the Convention and its Protocols, and benefit sharing should arise from its use. While there are differences of views, it is clear that every Party can decide through its national legislation whether and how to regulate access and benefit sharing for GSD. It is noteworthy that some national legislation already subject GSD to access and benefit sharing requirements. Given the relevance and importance of GSD for pandemic preparedness and response, it is crucial to handle GSD equitably at the multilateral level, failing which countries are likely to be reluctant to share such data promptly.]
An argument often put forward by the industry is that presently for the regulatory testing, PIP biological material is necessary, and hence the influenza vaccines developed solely from GSD are not an urgent matter to be addressed. This argument holds no weight as the PIPFw is about strengthening preparedness and hence decisions have to take into account future realities.
Monitoring use of GSD
dealing with GSD, a fundamental question that arises is how to monitor
its use, to especially ensure fair and equitable benefit sharing,
without hindering access to such data. This question has been studied
and discussed extensively by the PIP Advisory Group and related expert
groups, leading to identification of three options for monitoring
use GSD. These are:
(ii) The use of databases that enable identification of the GSD provider and flag the sequence as ‘IVPP GSD’;
(iii) The development of a search engine to identify end-products developed using GSD.
Of these options, it is important to note that the Technical Working Group on the sharing of influenza GSD set up by the Advisory Group to consider the “Optimal Characteristics of an Influenza Genetic Sequence Data Sharing System under the PIPFw” concluded that “In order to promote benefit-sharing under the PIPFw, all data users would ideally be asked to accept a data access and use agreement that would specify the obligations and expectations of the PIPFw.”
Data access and use agreement refers to online click-wrap agreement, widely used in the present digital environment. In the context of the PIPFw, for monitoring GSD it can be effective for highlighting expectations of the PIPFw, allowing identification of users of GSD, and requiring such users to agree to the terms of the Framework prior to accessing GSD. It is a tried and tested mechanism in the flu environment as it is utilised by the Global Initiative on Sharing Avian Influenza Database (GISAID), a database that hosts the large majority of influenza viruses for identifying users of GSD prior to allowing access to GSD. Thus far, such a mechanism has not hindered research.
Hence data access and use agreements should be explored as the viable option for monitoring the use of GSD that meets the objectives of the WHO PIPFw.+