Review Of WHO Pandemic Flu Preparedness: Data Sequencing And Other Issues

Five years after its adoption, a World Health Organization mechanism to help the world be ready for future influenza pandemics is being reviewed. According to several stakeholders invited to share their views, a major challenge is genetic sequence data, which allows digital reproduction of material. Other issues include the relationship of the mechanism to an international convention on access to genetic resources, and the contribution of industry.

The Pandemic Influenza Preparedness (PIP) Framework Review Group is meeting at WHO from 30 March to 1 April. On 30 March, the group sought views from different stakeholders on the achievement of the framework, its effectiveness in improving the global preparedness and capacity to respond to an influenza pandemic, and the existing challenges and how to address them. The webcast was available here.

The PIP Framework, which became effective in 2011, provides a mechanism to improve the sharing of influenza viruses with human pandemic potential, and at the same time increase the access of developing countries to vaccines and other pandemic-related supplies. This is achieved through an annual partnership contribution by industries using the framework to access the viruses, and agreements through which manufacturers decide on benefit-sharing options. Christine Mwelwa Kaseba-Sata

The PIP Advisory Group recommended in October that a small independent group of experts be established to review the implementation of the PIP Framework, according to the WHO.

The next meetings of the Review Group are from 9-11 May (closed meeting in Geneva), and 27-29 June (closed meeting in Geneva), then in September a consultation with stakeholders is expected to be organised. The final report is expected to submitted by the group on 31 October. The report will then be presented at the WHO Executive Board meeting in January 2017 and to the annual World Health Assembly in May 2017.

Member states are being urged to submit their views to the review group by email at: pipreview@who.int.

Genetic Sequence Data Might Jeopardise Benefit-Sharing

During the meeting yesterday, several issues were discussed, among them genetic sequence data (GSD). Technological progress now allows access to genetic material that has been sequenced into data, and the reproduction of this material without the need to access the physical form of the material.

The PIP Framework is based on the sharing of physical viruses. The availability of genetic sequence data in databases that can be accessed by anyone could potentially threaten the system of access and benefit-sharing. The WHO has been working on the issue for some time.

A representative from the Bill and Melinda Gates Foundation said the sharing and use of genetic sequence data should be discussed more comprehensively in light of the entry into effect of 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 (CBD).

A representative of the Francis Crick Institute, which is one of the WHO Collaborating Centres for Reference and Research on Influenza, praised the EpiFlu database, which contains an open source collection of influenza sequences, and was established with the support of the government of Germany. EpiFlu is hosted by GISAID. He said there is a distinction between publicly accessible data, and data made available through the public domain.

The WHO Global Influenza Surveillance and Response System (GISRS) has provided a trusted environment for sharing data, he said. EpiFlu is one of the database used by WHO collaborating centres to access information.

There is a need to consider that genetic sequence data is not covered by the PIP Framework at the moment and the review group should reflect on this possible inconsistency and whether genetic sequence data should be included as PIP biological materials, he said. The main concern is that “we must not undo the progress that has been made in the last ten years or so, and must not lose the confidence that has been built up in the GISRS system,” he said.

A representative of GISAID said one of the challenges of PIP Framework is the “thorny question on how to handle GSD … in relation to its use for developing commercial products and the sharing of benefits.”

One of the major contributions of the PIP Framework is to extend the benefits of GISRS activities to the world at large rather than just mainly to the developed countries using seasonal vaccines, he said.

He suggested that a tag be attached to the influenza viruses with human pandemic potential (IVPP) GSD on the database, which would alert any user intending to develop commercial products of certain obligations under the PIP framework related to the use of that data.

In relation to benefit-sharing, he said, “the intention is to develop simple tools on the database which will facilitate those individuals, less expert, in developing countries, to analyse their data in the context of the global data, in the same way as more expert individuals in labs in developed countries can.”

“In this way, we really build the capacity of the labs around the world to analyse their data in the same way and to understand the discussion that goes on whether it is in relation to the selection of influenza vaccine candidates, or the selection of potential candidate for pre-pandemic vaccines,” he said.

Industry, Civil Society Offer Different Views on GSD

A representative of Sequirus, one of the largest vaccine manufacturers, on behalf of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), the Biotechnology Innovation Organization (BIO), and another industry group, said industry supports the PIP Framework.

Genetic sequence data of influenza viruses with pandemic potential are not WHO PIP biological materials per the definition of PIP biological materials, the representative said. It is critical that GSD remain in the public domain for continued influenza R&D efforts, she said. In the context of the PIP Framework review, “industry is willing to consider an appropriate revision to the PIP biological definition to reflect anticipated technological advances.”

However, “not all influenza IVPP and IVPP GSD should be included in the definition and subject to the WHO PIP Framework obligations,” the industry representative said, rather only GSD which is used directly to develop and manufacture commercial IVPP products. “Attaching obligations to the general use and the sharing of publicly available GSD could potentially inhibit influenza R&D.”

In some cases, physical samples and/or GSD are used for R&D for non-influenza products and these should not be subject to the WHO PIP Framework, she argued.

“IFPMA and BIO strongly oppose any kind of mechanism to monitor, trace, and trace the general use of GSD, as this could potentially delay dissemination within the scientific community, inhibit influenza R&D, and be over-reaching burdensome and difficult to implement, said the representative. “Most importantly, it could hinder rather than bolster the progress towards influenza preparedness.”

On benefit sharing, another industry representative said the trigger for switching from seasonal to pandemic vaccine production is vital for the activation of the latest standard material transfer agreement (SMTA2), and industry requests clarification on the roles and responsibilities of which entity requests the switch from seasonal to pandemic vaccine production as it is not possible to make seasonal and pandemic vaccines at the same time.

SMTA2 refer to the transfer agreement for manufacturers who receive biological materials from the GISRS and ensures that those manufacturers and research institutions will share with WHO some of the benefits arising from their access to those materials.

On the issue of genetic sequence data, a Third World Network (TWN) representative said that “it is well established that GSD is part of the PIP biological materials and the framework.”

“If appropriate mechanisms are not developed to deal with GSD, the benefit sharing component of the PIP Framework may be adversely affected and the fundamental principle of the PIP Framework, of treating virus sharing and benefit sharing on an equal footing, [will be] undermined.”

TWN asked that “any database that wishes to host GSD should implement a common data access and use agreement that specifies the obligations of the PIP Framework and enables identification of the person that is downloading that specific GSD.”

“This is already being done today and it does not hinder sharing of data,” she said. “Instead, it creates confidence and facilitates rapid sharing of data.”

Partnership Contribution

The Gates Foundation representative highlighted the partnership contribution as a “major success” of the PIP framework, and hailed the PIP as a successful public-private partnership.

On the partnership contribution, one of the industry representative said it has been indexed on the running cost of GISRS.

“Industry requests that the review committee reconsider the GISRS running costs as a reference index for the partnership contribution, as some stakeholders advocate expanding the role of GISRS to other disease areas,” he said. He also suggested that the growth of partnership contributions be capped, and any increase should be linked to an appropriate economic indicator, such as the global GDP growth.

This idea of capping the growth of partnership contribution was questioned by TWN, which said that terms of the partnership contribution were negotiated as part of the PIP Framework, and in consultation with industry.

TWN voiced concerns that SMTA2 signed with larger manufacturers of vaccines and antivirals has not made sufficient progress, with only three companies signatories of SMTA2. The representative also remarked that among the different options of benefit-sharing, none of those three companies opted for royalty-free licences to WHO, which can be sublicensed for the production of pandemic influenza vaccines, adjuvants, antivirals products and diagnostics needed in a pandemic.

According to GISAID, there are a number of commercial users of GSD which could be contacted through the PIP secretariat and encouraged to participate in the framework.

Anne Huvos, from the PIP secretariat, said the secretariat started off by reaching out to large multinational vaccine manufacturers with large production capacity. Those companies were quite familiar with the PIP Framework, she said, however it took between 9 and 18 months to conclude an agreement.

The situation is different for small to medium-sized companies that are not familiar with the PIP Framework, and do not know what it means to produce for the UN under prequalification. Several factors then come into play beyond prequalification, she said, such as labelling, translation of labels, export packaging and all features relating to the export of vaccines from the national system to the international system, she said.

Most smaller producers have advance purchase agreements with their host countries, and their production is tailored to fulfilling the need of that market. If they need to increase their production capacity, they often need to go back to their government and negotiate with them how to devote some production capacity to the WHO, she explained.

Relationship with Nagoya Protocol

An industry representative said industry is concerned about linkage between the Nagoya Protocol and the access to genetic resources under the Convention on Biological Diversity, and the WHO PIP Framework. The representative said the lack of clarity on how the protocol and the PIP Framework interact may lead to legal uncertainty for member states and industry, and a potential decrease in the validity of the SMTA2.

TWN countered that the relationship between the PIP Framework and the Nagoya Protocol is clarified in the principles of the PIP Framework Paragraph 7 (“…recognize this Framework is to be implemented in a manner consistent with applicable national and international laws, regulations, and obligations”), and Paragraph 11 (“recognize the sovereign right of States over their biological resources and the importance of collective action to mitigate public health risks”).

The Nagoya Protocol hinges on prior informed consent and mutually agreed terms and the PIP Framework creates that prior informed consent and mutually agreed terms, TWN said. These are not new issues, as they were discussed during the process of the PIP Framework negotiations, she said.

Industry suggested that the review group discuss a recommendation supporting the elevation of the GISRS and the PIP Framework to the status of “specialized access and benefit-sharing agreements” as described in Article 4.4 of the protocol. That should be decided by CBD and Nagoya Protocol members, she said.

Article 4.4 includes the following: ” Where a specialized international access and benefit-sharing instrument applies that is consistent with, and does not run counter to the objectives of the Convention and this Protocol, this Protocol does not apply for the Party or Parties to the specialized instrument in respect of the specific genetic resource covered by and for the purpose of the specialized instrument.”

Without legal clarity on the linkage between the Nagoya Protocol and the PIP Framework, it could happen that PIP biological materials are not made available to the WHO or vaccine and medicines manufacturers “in a timely way, or possibly at all.” she said. It is also possible that manufacturers could perceive greater risk in conducting R&D, or produce vaccines with such materials for fear of violating the Nagoya Protocol parties’ access and benefit sharing legislation stipulating administrative or criminal penalties for unauthorised use of such materials, she added. The implications on pandemic influenza preparedness and response “may be grave.”

End of GAP – Should PIP Include Some Elements, Be Expanded?

The representative of the Gates Foundation underlined the “huge success,” of the Global action plan for influenza vaccines (GAP), expected to end at the close of 2016, while other speakers underlined issues with the programme. He advised that the review group look at synergies between the GAP and the PIP and what objectives of the GAP could be achieved through provisions of the PIP Framework. This was supported by industry.

TWN, meanwhile, said both GAP and the PIP Framework seek to address issues relating to pandemic influenza, but not in the same way. The review of the GAP underlined issues and failures in GAP, she said, and if some elements from GAP were to be taken to the PIP Framework, it should be done very carefully, she said, because the GAP did not really deliver on its goals.

The Gates representative also called for the Review Group to consider including seasonal influenza viruses into the PIP Framework.

TWN advised against expanding the PIP Framework to other diseases or to seasonal influenza.

“The PIP framework should set a course to further the progress made in the PIP Framework and we should not dismantle what has been done,” the TWN representative said. Any extension should consider additional components of benefit-sharing, partnership contribution, and SMTA2.

However, TWN said a number of lessons can be learned from the PIP Framework and applied to other diseases. There is a gap in terms of regulations, the representative said, citing severe acute respiratory syndrome (SARS), and then the Middle East respiratory syndrome (MERS), then Ebola, and Zika.

Issues such as intellectual property, sharing of information, access to and affordability of vaccines are raised for each new disease, she said, calling for a specific framework for other pathogens, and defining the role of WHO in the event of emergency.

Christine Mwelwa Kaseba-Sata, chair of the Review Group, called for a collaborative effort. “No one actor is going to make the world a better place,” she said. “We do not know when the next pandemic is coming, but it will come,” and all affected countries should be in a position to respond to the pandemic.

It is essential to have robust surveillance systems, that all countries share viruses with WHO GISRS, and equally important that countries benefit from the sharing of those viruses, she said.