5
Accelerating Research and Development to Counter the Threat of Infectious Diseases
The increasing threat of emerging and reemerging infectious disease outbreaks demands research and development (R&D) of effective and fit-for-purpose tools and technologies, such as vaccines, drugs, diagnostics, personal protective equipment (PPE), and medical devices. Recent epidemics have highlighted gaping holes in our ability to rapidly deploy medical products that will not only help identify and contain outbreaks, but also care and treat those affected. To ensure successful resolution of the next major outbreak with minimal loss of life, we must have a more robust R&D strategy.
This strategy should include, at a minimum, a defined coordinating entity; an investment plan for a comprehensive portfolio of medical products; convergence of regulatory requirements across countries or regions for testing, approval, and licensure of new products; agreements on access to intellectual property (IP), if any, and to data and materials, manufacturing capacity, and distribution channels; and the incorporation of social and political considerations for the successful adoption of technologies and best practices at local levels. Experience has demonstrated that without substantial community engagement and anthropological research, effective technologies may not be readily and swiftly adopted to curtail spread of disease (Tindana et al., 2007).
A PANDEMIC PRODUCT DEVELOPMENT COMMITTEE TO DRIVE THE R&D STRATEGY
Readiness for infectious disease outbreaks requires ongoing investment in research in myriad disciplines, including basic biomedical research to understand the etiology of disease, the causative agents, the symptomatology, clinical research to test for safety and efficacy of potential new vaccines and drugs, and anthropological research to identify the contributing social and cultural factors. Crucially, the development of appropriate PPE, point-of-care diagnostics, and a portfolio of novel therapeutic agents, including for antimicrobial resistance (AMR), and vaccine constructs that can be quickly brought to scale, must take place before a crisis strikes, rather than in the midst of an outbreak.
In parallel, population, policy, and implementation research is needed to understand the population factors, policies, and delivery systems that work best for scaling up interventions to improve the delivery of biomedical interventions (Jamison et al., 2013). In particular, social research, involving local capacity building where necessary, must be undertaken at vulnerable hotspots to anticipate potential outbreaks, generate vital information about the causes of infection, and develop a body of work that can usefully inform the design and implementation of interventions in future emergencies. It is clear that such a comprehensive approach will only succeed with the contributions of multiple parties working toward common goals.
Pandemic Product Development Committee
In times of global health emergency, the R&D community—academia, government, industry, and civil society—must be galvanized as a cohesive group to swiftly determine the necessary biomedical interventions. For example, in the short term, identification and diagnosis of the pathogen, as well as selection of existing tools to treat and control the infection and curtail AMR,
are critical. However, it is likely that current technologies will prove insufficient or ineffective, and, therefore, a massive effort to find the needed tools must be undertaken (Balasegaram et al., 2015; Jamison et al., 2013). When there is no pressing emergency, the R&D community has to continue to develop knowledge and have products ready for scale-up and distribution. These activities must be coordinated to ensure effective prioritization, maximize the possibility of success, reduce redundancy and cost, and save lives. However, to date, there are only weak coordinating mechanisms to perform these activities, despite longstanding recognition of this unmet need (CEWG, 2012; CHRD, 1990; CIPIH, 2006). The consequences of the lack of coordination were exposed again in the recent Ebola outbreak, causing confusion about how best to approach and implement response efforts and thereby contributing to inefficiencies (WHO, 2015c).
In line with its constitutional mandate to direct and coordinate international health work, the World Health Organization (WHO) should galvanize the acceleration of relevant R&D to counter infectious disease threats by establishing a high-level, broad-based expert panel, an independent Pandemic Product Development Committee (PPDC), which would be accountable to the Technical Governing Board, or TGB (see Chapter 4 for more on the TGB). The PPDC would be independent of WHO, and make decisions according to the advice and views of its members, appointed for their technical expertise, not under the direction of WHO. Such a coordinating entity would help fill the unmet need by pinpointing existing capabilities, identifying gaps, and determining priorities for a concerted global effort to develop, test, manufacture, and distribute the relevant medical products in cases of emergency.1 The PPDC should be focused primarily on diseases of pandemic or epidemic potential, including coronaviruses and influenza viruses, among others. The committee’s roles and responsibilities should include identifying R&D priorities to tackle high-risk pathogens2 and monitoring the distribution of funds allocated to the PPDC in line with these priorities. Additionally, the PPDC would be charged with drafting the emergency preparedness plan that outlines R&D roles and responsibilities as part of the overall response. Specifically, this plan would provide a clear roadmap for all willing contributors to the effort, including, but not limited to, identifying existing technologies and best practices; determining “who does what when”; selecting and enabling a central emergency point of contact; establishing and implementing a far-reaching, trustworthy communications strategy; and maintaining close contact with on-the-ground responders, governments, industry, scientists, clinicians, and civil society, among others. Domain experts from key stakeholder organizations should be called on to support the many activities the PPDC undertakes, but the PPDC would not be charged with direct management of any specific projects. The TGB should assess the PPDC performance on a yearly basis.
The Commission recognizes that the PPDC must consider the impact of AMR on preparedness efforts. As we have seen with human immunodeficiency virus (HIV), tuberculosis, and other infections, resistance will eventually develop, creating an added challenge for com-batting disease and disability. AMR is the by-product of indiscriminate use of antibiotics in the animal industry and human medical practice. Indeed, it is a manmade disaster (IOM, 2010) due to gross misuse of high-quality drugs as well as widespread use of counterfeit antibiotics in many parts of the world. Thus, although the focus of the PPDC must be addressing pandemic threats, the actions it takes can and must be aligned with steps to address resistance. This synergy will serve patients, communities, and countries well.
The WHO Director-General should appoint the chair of the PPDC and, in collaboration with the chair, appoint the committee members. The chair should be an R&D expert who is also a member of the TGB and would help spearhead resource mobilization. Members should include, at most, 15 internationally recognized leaders who have expertise in discovery, development, regulatory review and approval, and manufacturing of medical products. These experts should be affiliated with pharmaceutical and biotechnology companies, foundations, academia, research institutions, clinics, and patient
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1 WHO is in early stages of developing a new R&D Blueprint with similar aims to capture existing knowledge and good practices, identify gaps, and create a roadmap for R&D preparedness, but does not have an entity like the PPDC to take the lead (WHO, 2015a).
2 A panel of scientists and public health experts convened by WHO has developed an initial list of disease priorities needing urgent R&D attention, which will form the “backbone” of the new WHO Blueprint for R&D Preparedness (WHO, 2015d). The list of priority diseases includes Crimean Congo hemorrhagic fever, Ebola virus disease, Marburg hemorrhagic fever, Lassa fever, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronavirus diseases, and Nipah and Rift Valley fever.
and civil society groups.3 The members should serve in their personal capacity in a process that is transparent and balanced. In addition, to ensure impartial decision making, members must disclose any conflicts of interest or potential conflicts of interest before a decision is made on the matter involved, and should be prohibited from voting (other than by offering information) on any decision in which there is a conflict. Information about the members, including those that could be determined to have a potential conflict of interest, should be published on the WHO website.
Further, a few WHO representatives should participate and provide secretariat support for the PPDC. While the Commission appreciates the complexity of creating and implementing such a group, the clear expectation is that the secretariat would have an enabling role and would be highly sensitive to the importance of ensuring minimal, albeit adequate, spending on administrative infrastructure, thus maximizing the amount of funds devoted to R&D needs. These representatives must have high-level technical expertise and relevant experience in R&D of medical products and possess experience derived from tenure in industry, academia, and/or relevant government agencies.
Recommendation D.1: By the end of 2016, the World Health Organization should establish an independent Pandemic Product Development Committee, accountable to the Technical Governing Board, to galvanize acceleration of research and development, define priorities, and mobilize and allocate resources.
ACCELERATING R&D BY INVESTING $1 BILLION PER YEAR
Achieving significant acceleration in R&D related to pandemic and epidemic diseases requires significant amounts of new money. Because it is critical to use the best science to strengthen global defenses against the threat of potential pandemics, the Commission recommends targeting incremental spending of $1 billion4 per year for at least 15 years. Used synergistically with existing and new expenditures in the public and private sectors, these funds would provide a strong foundation for the development and production of an armamentarium of medical tools, including diagnostics, vaccines, drugs, equipment, and techniques, to build and sustain R&D preparedness capacity for rapid response to global infectious disease outbreaks.
The $1 billion figure can be compared to the scale of a small–medium pharmaceutical company’s R&D portfolio of promising drugs and vaccines for key target diseases that are in various stages of development.5 At this size, when there is an outbreak of a known pathogen, much of the early research work would have been completed, and it will then be possible to move some of the products quickly to clinical testing, regulatory approval, production, and deployment.
To build better defenses against the threat of pandemics, we must step up the pace and scale of R&D on infectious diseases. It is imperative, therefore, to invest in a portfolio of platform technologies and facilities, using public funds where necessary and appropriate and leveraging commercially driven investment where possible. Given the accelerating emergence of new pathogens and the reemergence or geographic spread of previously contained agents, the program must support simultaneous development of multiple platforms. In some cases, it will make sense to take products through to full commercialization; in others, where the threat is more distant, it may be optimal to pause at a certain point, leaving full development and licensing until the threat appears more proximate.
It is important to note that the PPDC’s role should go beyond purely pharmaceutical R&D. The PPDC should shape and oversee an R&D program that encompasses equipment; instruments and tools, such as low-cost diagnostic kits; surveillance systems; and PPE. The PPDC should also help streamline the product development infrastructure required to enable accelerated clinical trials and approvals, as well as promote innovations to enhance manufacturing technology and capacity and deployment systems. However, the PPDC would not deliver the products itself—delivery would be carried out by whomever is allocated the responsibility. The Biomedical
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3 Although WHO has had difficulties in directly engaging with non-state actors, such as private-sector companies, the Commission believes that with the adoption of the Framework for Engaging with Non-State Actors (FENSA) and Recommendation C.6 (explained in Chapter 4), WHO can take genuine steps to engage non-state actors for this effort.
4 All monetary figures in U.S. dollars.
5 The $1 billion figure is derived from Commission expertise and does not include a precise number for each product in the portfolio, as the number and types of products fluctuate in any given year, making it unrealistic to make such calculations.
Advanced Research and Development Authority of the U.S. Department of Health and Human Services, which has experience managing the advanced procurement and development of medical countermeasures for pandemic influenza and other emerging infectious diseases, would be a valuable source of know-how and best practices for the PPDC. The recent Ebola crisis revealed many deficiencies in the global product armory, from diagnostics to vaccines to PPE—and this is for a virus discovered nearly 40 years ago. Only now are we approaching the successful development of an effective vaccine.
In a sense, we should take an approach akin to that of advanced defense organizations, which anticipate future threats, envision countermeasures, and invest in R&D, both directly and by galvanizing private industry. For example, the U.S. Department of Defense (DOD) spends $70 billion on R&D (AAAS, 2015). Indeed, reflecting its assessment of future threats to the U.S. population, the DOD has been one of the larger sources of funding for infectious disease research. Comparison with defense R&D also helps put the $1 billion figure in perspective. As we argued in Chapter 2, the global community invests far less in protecting human lives and livelihoods from the threat of infectious diseases than it does in countering other threats, such as wars, terrorism, and financial crises.
By coordinating incremental R&D investments, we can maximize their impact. We anticipate that the $1 billion would comprise two different components: one portion would come from stakeholders who delegate decision making on deployment of finances to the PPDC, the second from other stakeholders who retain control over the deployment of funds, but work closely with the PPDC to achieve better coordination. Through collaborative shaping and prioritizing of discrete research programs into an overall R&D strategy, the PPDC would help ensure focused efforts in areas of maximum impact across the infectious disease spectrum, not just areas that happen to be commercially viable or fit existing research agendas. The optimal balance between the two components of funding would be determined in detailed discussion with potential contributors.
Investments in Three Key Areas
The PPDC, in coordination with other funders, would aim to deploy the funds in the following three key areas:
- Development and strengthening of core functions. These are investments in infrastructure and capabilities needed by all R&D stakeholders, such as high-throughput screening, formulation technology, manufacturing capacity, and building strong local research capacity where outbreaks are likely to occur.
- Targeted expansion or acceleration of ongoing R&D projects. Recent outbreaks have shown the need to create and test potential new platforms for vaccines and novel drugs past Phase I (safety) trials and primed for Phase II (efficacy) trials once a potential emergency is identified. Investment in and development of platforms already being pursued by government agencies, industry, and foundations would allow a nimble, “plug and play” strategy because process development, chemistry, manufacturing, regulatory controls, and analytics would already be in place. Likewise, investments in effective surveillance technologies; point-of-care diagnostics; PPE; medical devices; and population, policy, and implementation research are also strongly needed. Again, expansion or strengthening of existing investments in these areas is paramount.
- Innovation. Without new scientific knowledge and the synergistic integration of multiple disciplines, new product development and disease-prevention strategies would be impossible. For example, it is imperative to identify new targets for antibiotic development; find ways to potentiate immunological responses; craft strategies to integrate “omics” into tool development; develop continuous manufacturing techniques; validate novel clinical trial designs; integrate information and communication technologies into strategies that better track the emergence and diagnosis of global health threats; and discover new platforms that would have broad applicability to identify, prevent, and/or treat infectious diseases with pandemic potential.
Taken together, these three investment areas can produce technologies that are fit-for-purpose and a comprehensive strategy to address threats nimbly and quickly.
Sources of Funding
The Commission envisions that the $1 billion for R&D could be drawn from five potential sources6:
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6 A detailed roadmap on how the funds are mobilized, coordinated, sustained, allocated, and monitored is beyond the scope of this report and will be ultimately up to the PPDC to decide on these
- Direct contributions from national governments, foundations, and the private sector, including private finance from outside the health care sector (see potential source number 5). Such investments have the advantage of leverage and have proven very successful in creating public–private partnerships such as Gavi, the Global Health Innovative Technology Fund, the Global Alliance for TB Drug Development, the Drugs for Neglected Diseases initiative, and the Medicines for Malaria Venture, among others.
- From R&D budgets devoted to national security. The role of the DOD, such as through the Defense Advanced Research Project Agency and Defense Threat Reduction Agency, is a model. More countries should recognize that infectious diseases represent significant threats to national security and deploy resources accordingly.
- From existing public, philanthropic, and university R&D budgets in the health arena, particularly funds for pandemic threats. When combined, these can boost the individual investment capacity and create important synergies. This potential amplification would help address the severe constraints on current budgets.
- By catalyzing private-sector R&D. Economic drivers enable R&D for infectious diseases for which there is strong market demand—these include, for example, nosocomial infections and yearly flu vaccines. However, sustained private investment for R&D for potential pandemics that may or may not surface or for which testing and licensure is difficult is unlikely. Nevertheless, the private sector has demonstrated a willingness to contribute to the global effort in myriad ways, including through donation programs, by activating R&D capacity in times of crises, and by providing infrastructure support, human resources, and direct funding—making them important contributors to these efforts (WEF, 2015).
- Generating new sources of private finance from outside the health care sector. All sectors of the economy suffer the consequences of a serious epidemic or pandemic. Therefore, all businesses have a direct interest in supporting tax-funded public spending to mitigate this significant threat. For some types of businesses, there are even more direct connections. For example, the insurance industry faces a significant risk, given the potential impact on mortality; travel and tourism stand to suffer, given the sector’s acute vulnerability to restrictions on travel which might be imposed, as well as to voluntary infection avoidance behaviors; and, of course, the meat and poultry trades face the threat of losses due to disease or mandatory culling in the event of an outbreak. One specific example of a novel funding source that could be worth investigating arises from the fact that life insurers hold capital against extreme mortality risk scenarios, among which pandemics are the most likely events. In principle, firms offering life insurance products should be able to reduce their exposure to such risks by funding research, which accelerates the R&D of products that reduce the likelihood of mass mortality pandemic events. If regulators were to approve reductions in reserve requirements faced by such firms due to a lowered risk of pandemic-related mortality, funding such research would appear doubly attractive. Such ideas undoubtedly warrant further exploration.
Recommendation D.2: By the end of 2016, the World Health Organization should work with global research and development stakeholders to catalyze the commitment of $1 billion per year to maintain a portfolio of projects in drugs, vaccines, diagnostics, personal protective equipment, and medical devices coordinated by the Pandemic Product Development Committee.
ENSURING CONSISTENT STANDARDS FOR RESEARCH DURING CRISES
When a major outbreak occurs, appropriate medical products may be not fully developed or ready for deployment to affected areas. Therefore, there is a strong need to rapidly develop and evaluate investigational therapies during outbreaks, to identify those that benefit patients, and to protect against those that cause harm. To test these therapies and products, researchers have used
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mechanisms. The Commission recognizes the challenges in raising this scale of funds proposed and achieving the level of coordination envisaged. However, the Commission believes that accelerating R&D in this arena is of such importance that this is worth trying.
a variety of approaches to conduct studies (Borio et al., 2015). Some of these approaches have led to uninterpretable results and invalid conclusions. Some have also resulted in misunderstandings and suspicion on the part of participants due to poor engagement with communities. In this section, the Commission discusses the need for researchers to conduct scientifically rigorous research studies and to engage locals for studies conducted in community settings.
Commitment to Scientific Standards
The Commission recognizes the natural tension between the immediate needs of health care workers in the field having to treat the sick and the imperative to conduct trials and studies to ascertain the safety and efficacy of new medical interventions. Society has an obligation to provide immediate help to those in need and to protect health care workers and first responders. But example after example—including the AIDS pandemic, SARS, MERS, and the recent Ebola outbreak—also show that in conducting clinical trials for new vaccines or drugs, society must ensure that in all instances, particularly during health emergencies, these studies are scientifically sound and justifiable and yield interpretable data and strong, valid conclusions.
Researchers must conduct trials under rigorous scientific and ethical principles. Randomized controlled trials (RCTs) offer robust methodology with low probability of bias or confounding. RCTs also best utilize the limited number of experimental interventions by obtaining the most valid and reliable results for the benefit of current and future patients (Kalil, 2015). If data are poor and controls are weak or nonexistent, information about how experimental products may be helping or harming current patients remains unknown, offering no benefit to future patients and potentially causing harm.
Different and innovative trial designs can be—and are—employed to allow for interpretable, scientifically sound results. For vaccines, two examples of such trial design include the immediate-versus-delayed-vaccination and “ring” vaccination trials, which were conducted in Sierra Leone and Guinea, respectively, during the Ebola outbreak (WHO, 2015b). For therapeutics, the National Institutes of Health’s (NIH’s) medical countermeasures study contains multiple intervention arms with just one placebo (i.e., standard-of-care) group. This “adaptive” design allows trial arms to stop early where there is demonstrated toxicity or lack of efficacy (Borio et al., 2015). During public health emergencies, these adaptive trial designs may help balance the need for scientifically valid information and rapid results. However, no trial will benefit the public if data and results are not shared in a timely manner so that they can be reviewed and validated by external investigators and regulators. Therefore, regardless of the trial design, data and results of all trials must be shared promptly and transparently.
To conduct these trials, a strong local clinical trial infrastructure is paramount. Unfortunately, in many resource-poor countries, particularly in hotspots for emerging infectious diseases, trained staff, appropriate technical support, and adequate physical facilities are completely lacking—hampering the swift movement of potentially useful products from Phase I or Phase II into Phase III trials. Preparedness for trials requires appropriate physical infrastructure, a trained health care workforce, established and functional ethics committees, expertise in social sciences, community mobilization, and sustainable basic public health capacity, such as surveillance and basic laboratories. This takes time and resources. If we are to be ready for the next outbreak, we need to assess the current research and public health capacities of vulnerable areas and invest in building this infrastructure. The PPDC could provide guidance on the funding and delivery mechanisms of such an effort.
Engaging Communities in Research
When researchers design and conduct studies in community settings, strong local engagement and buy-in is imperative at every step along the way. Involving local people, particularly key opinion leaders and scientists, is of critical importance; in many communities, for example, local healers as well as religious and peer leaders are enormously influential (Awunyo-Akaba, 2015). Open, bilateral, or multilateral information exchange from the outset will create trust, promote discussion, help address local concerns or misperceptions, and ensure that study participants are treated with utmost respect and consideration.
As researchers seek to enroll participants in studies, care must be taken to ensure that participants are fully informed and educated about all aspects of the protocol. This process is not always straightforward (Geissler and Molyneux, 2011; Parker and Allen, 2013), but it is essential. Informing study participants necessarily requires
proficiency in the local language, regular dialogue with study participants, meetings with experienced local scientific investigators, and an understanding of the way in which the political reality shapes participation at the local level (Sow, 2015). Every effort should be made to inform local leaders, as well as civil society groups, about the science of the disease and the rationale underpinning the design of the particular clinical trial. Such an approach is not only invaluable in itself—it also helps to mitigate rumors and misunderstanding.
A program run by the Kenya Medical Research Institute–Wellcome Trust Research Programme usefully illustrates the way in which study participants in international health research acquire relevant knowledge before consenting to participation in a trial. This program engages local community facilitators, health care professionals, and local people to create consent forms that are socially and culturally sensitive to local needs (Boga et al., 2011). By bringing together community stakeholders, the initiative confronts concerns about research head-on and incorporates potential solutions into the consent process. Concerns can range from understanding of controls and placebos to sample storage and use, among other scientific or process-based issues (Boga et al., 2011).
The emphasis on creating and maintaining open dialogue between those doing the research and those participating in the study is critical. Under its Communication for Development initiative, the United Nations Children’s Fund (UNICEF) encourages social mobilization as an effective approach to informing communities. This approach brings together local stakeholders to learn about particularly relevant issues through open dialogue (UNICEF, 2015). Opening up a conversation allows researchers to address local anxieties and fears, alter their messaging accordingly, and ensure that people truly understand the purpose of the research.
Even if there are effective medical products available following the conclusion of a study, the products are useless if they are received with suspicion, rejected by those residing in affected areas, and ultimately not adopted for use. Widespread fear and anxiety, occasionally leading to violent rejection of mass drug administration for control of neglected tropical diseases, as in the case of schistosomiasis (Hastings, 2016; Muhumuza et al., 2015; Parker et al., 2008) and lymphatic filariasis (Kisoka et al., 2015; Parker and Allen, 2013), usefully illustrates this point. Thus, researchers must establish and maintain relationships with local individuals to effectively move a study or product forward. Further, strong communication must be matched with successful service delivery to be effective. In order to achieve this, researchers and product developers must engage local logistics support, supply chain experts, and those with knowledge of the specific social contexts in which supplies will be delivered and dispensed (Hall, 2015).
SECURING OVERARCHING GLOBAL AGREEMENTS TO EXPEDITE APPROVAL, MANUFACTURE, AND DISTRIBUTION
Under the coordinating leadership of the PPDC, R&D stakeholders should pre-negotiate global agreements to facilitate timely and appropriate implementation and distribution of a range of tools and infrastructure during a global infectious disease outbreak. Without agreement on regulatory approval and review, manufacturing and distribution mechanisms, indemnification, IP and data sharing, to name a few, effective medical products may not reach those in need.7
Convergence of Regulatory Processes and Regulatory Science Standards
Regulatory agencies must continue to work toward common rules, agree on best practices, and establish standards that will define how products for emergencies are reviewed and approved. Currently, each country has its own distinct processes of reviewing and approving the safety, efficacy, and quality of medical products. Understanding and navigating the diverse regulatory systems can be cumbersome and complex, causing delays in deploying products to patients. A streamlined process across regulatory systems would lead to important efficiencies.
The problem of discordant regulatory systems was illustrated during the H1N1 outbreak, when each country’s national regulatory authority—understandably—imposed its own regulatory process for approving, authorizing the importation, and overseeing the distribution of vaccines. Processes ranged from one-time waivers of certain rules to detailed requirements for pediatric subgroup data, regulatory assessments capacity, quality
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7 The Commission recognizes that the following section does not lay out an exhaustive roadmap of how to achieve these agreements. Such a roadmap requires extensive discussion and analysis among various stakeholders and is beyond the scope of this report.
control preparedness and capacity, and post-marketing safety surveillance and field assessment of efficacy and immunogenicity (Halabi, 2015). Additionally, in over half of the beneficiary countries, prequalification of a vaccine by WHO was not sufficient to obtain regulatory approval, while in others, albeit relatively few, national laws stated that products donated by the UN did not require national registration (WHO, 2010). The distinct requirements that varied across countries adversely affected efficacious donation and distribution, as it took time for manufacturers and other entities to access, understand, and sift through the information on the countries’ regulatory processes and negotiate with regulators.
Regulatory convergence does not require nations to give up their autonomy, but rather helps them come together quickly to address the following questions: How can countries divide the tasks associated with a product review and work together to ensure that prescribing information is aligned? How can regulators align expectations of what is required in regulatory submissions for product review and approval? How can they move toward more common data and evidence standards? What are the knowledge base and the regulatory tools necessary for more streamlined oversight?
Some steps have been taken to achieve better regulatory convergence. In the most recent Ebola outbreak, regulators from around the world, including Health Canada, the United Kingdom’s Medicines and Healthcare Regulatory Agency, the U.S. Food and Drug Administration, and the European Medicines Agency, worked together with local regulators to speed preparation for trials in West Africa (EMA, 2014; WHO, 2015c). Another example is the International Coalition of Medical Regulatory Authorities (ICMRA), which is a voluntary, executive-level entity that provides direction for a range of areas that are common to many regulatory authorities’ missions (Skerritt et al., 2015). While ICMRA is still in its nascent stages, it may be a promising example in regulatory convergence, alignment, and standards development.
Pre-Approval of Clinical Trial Designs and Master Protocols
R&D stakeholders should discuss and agree on the different possible designs for clinical trials and protocols that are scientifically valid and appropriate for emerging infectious diseases. This would expedite the evaluation of investigational products during emergencies and allow therapies shown to be safe and effective to reach patients more quickly.
Currently, the process of approving clinical trial designs and protocols during an outbreak is not streamlined. This was apparent during the recent Ebola outbreak, when researchers worldwide diverged on the types of clinical trials to undertake and wrote protocols that took time to be approved in the three affected West African countries (WHO, 2015c).
The process of testing an investigational product would be more efficient if research clinical designs and protocols that took account of uncertainty were outlined and approved prior to emergencies and then adapted to the specific outbreak. Pre-approved clinical designs have been used successfully, such as when Médecins Sans Frontières assessed the validity of new rapid diagnostic tests during a meningitis outbreak, which reported no harm to participants and enhanced the ability of researchers to respond in a timely manner (Schopper et al., 2015). A move toward common protocols (Borio et al., 2015) and sharing designs and protocols broadly within the research community would allow researchers to be ready to test investigational products at the onset of a crisis. The International Severe Acute Respiratory and Emerging Infection Consortium, which provides a platform for researchers to share and download research protocols and data tools useful in epidemics, could help facilitate the pre-approval process and sharing of protocols (ISARIC, 2015).
Mechanisms for Managing Intellectual Property and Sharing of Data and Reagents
Transparent mechanisms for managing IP and sharing of data and materials are needed for efficient R&D processes during major outbreaks. Withholding valuable information, including negative results, is a disservice to the R&D effort; such behavior delays progress in the fight against the pandemic, wastes time and resources, and stifles collaboration (Heymann et al., 2015).
An example of a mechanism to streamline activities is WHO’s Pandemic Influenza Preparedness Framework, which seeks to improve and strengthen the sharing of influenza viruses with human pandemic potential (WHO, 2011). This requires manufacturers to agree on a standard material transfer agreement that regulates the terms under which countries agree to donate influenza samples, the entities authorized to receive and research
them, and the corresponding sharing of resulting vaccines and other IP. This framework oversees the sharing of H5N1 and other influenza viruses with human pandemic potential, but does not apply to non-influenza biological materials. This type of framework of sharing specimens could be expanded to other threats.
Likewise, data and other information related to R&D should be made available in a public domain to avoid duplicative costs and wasted effort. There are examples, such as GlaxoSmithKline’s data transparency model,8 the Global Alliance for Genomics and Health,9 and the Biomarkers Consortium,10 that have made important strides to ensure that information is promptly available to the public. In addition, the NIH, the U.S. National Science Foundation, The Bill & Melinda Gates Foundation, and the Wellcome Trust, among others, have established guidelines for data sharing by grantees. These models should to be expanded to make data sharing and speedy publication the norm.
Reasonable Protection Against Product Liability Claims
Stakeholders must agree on the degree to which manufacturers should be indemnified against liability claims during an emergency. Without realistic protection, many manufacturers will halt the production of medical products, and patients will not receive timely proper care or treatment.
Experience has shown that manufacturers require protection. During the H1N1 outbreak, for example, vaccine manufacturers required that all purchasers or recipients indemnify them for adverse events resulting from use of the vaccine, unless the failure was due to discrete manufacturing specifications (Halabi, 2015). In other cases, some manufacturers will not authorize the use of a vaccine for a clinical trial if they are not insured against legal liabilities or in the absence of clear agreements for protection. Even in situations where a manufacturer agrees in principle to donate to WHO or other UN agencies to protect from potential liability claims, it might not do so in certain countries if such vaccine is not duly licensed (GAO, 2008). Other legal barriers include those related to preexisting advance market commitment agreements, which affect the ability to enter into additional contracts once a pandemic has been declared, or those related to approval and registration procedures with national regulatory authorities (Halabi, 2015).
Identification and Contracting Manufacturing Platforms and Facilities
The PPDC should establish mechanisms to quickly identify and contract manufacturing platforms and facilities before and during a crisis. Such manufacturing capacity is not widely available, particularly in developing countries. Only a few areas of the world, such as Australia, Europe, Japan, and North America, have plants for manufacturing influenza vaccine (Halabi, 2015). In fact, the capacity for vaccine production is severely limited compared with the number of doses that would be required for a future pandemic.
Manufacturing takes time, resources, and expertise; different facilities are needed for different products. Therefore, accurate and detailed information on capabilities and output yields is crucial so that, in the event of a pandemic, R&D stakeholders will know if and when they can contribute to scale-up, how to produce the greatest possible quantity of medical products in a timely manner, and when and how to scale down safely after the threat disappears. Demand forecasting and clarification of stockpiling plans are also important in ensuring adequate production of drugs and vaccines. Spare manufacturing capacities may be needed to accommodate mass manufacturing of products, as well as testing investigational products. For example, GlaxoSmithKline has plans to share a manufacturing site where the scientific and pharmaceutical communities can come together to draw expertise and knowledge from the facility—from vaccine design through manufacturing (GSK, 2015).
If adequate manufacturing capacity is unavailable in an affected country, regional manufacturing and stockpiles could facilitate production and distribution of medical products to populations in need. In fact, specific centralized production facilities in countries with capable regulatory authorities and a track record for high-quality standards may be preferable in some areas for ensuring public health benefit in terms of quality, timelines, economies of scale, and affordability. These locations should be determined prior to an emergency. Indeed, it is reasonable to assume that attempting to build manufacturing and distribution infrastructure during an
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8 For more information, see http://www.gsk.com/en-gb/behind-thescience/innovation/data-transparency (accessed March 24, 2016).
9 For more information, see https://genomicsandhealth.org (accessed March 24, 2016).
10 For more information, see http://www.biomarkersconsortium.org (accessed March 24, 2016).
emergency will not yield best results—far from it. Taking guidance from national defense–enterprise preparedness strategies, the PPDC should consider finding ways to maintain a geographically distributed “warm industrial base” that is primed for quick scale-up of medical product manufacturing, deployment, and delivery where such products are most needed.
Access and Distribution of Stockpiles of Vaccines, to Reach Those at Greatest Risk
A global access framework should be developed to ensure that the right drug is delivered to the right place and population at the right time. As noted before, the sobering truth is that there is limited capacity for producing potentially lifesaving vaccines, and not everyone is able to get needed medical products at the same time (Yamada, 2009). This requires difficult decisions about who gets the medical products first.
The ability to pay should not determine where products are distributed, as in the case of a country that wishes to stockpile vaccines for its low-risk population. Rather, those who are at the greatest risk and in imminent danger during a crisis—whether they are frontline health workers or a vulnerable local population—should have priority. This means that, in order to ensure equitable access and distribution of vaccines to those in need, countries must refrain from nationalizing their vaccine manufacturing output. This was illustrated during the H1N1 outbreak in 2009, when governments with preexisting contracts sought to preserve the capacity of firms located within their territorial borders to inoculate their own citizens before giving or selling to other countries (Fidler, 2010). The rationale, which is understandable, was that the governments had an obligation to their citizens before exporting vaccines to other populations. However, the reality was that these populations were at very low risk and the prioritization was incongruent with good public health policy.
To ensure access, a process for stockpiling supplies of premanufactured material should be developed. In addition, prices need to be such that the most vulnerable people, who tend to be the poor, can afford the medical products. Contributions from high-income countries to offset the cost of vaccines for countries and populations who cannot afford to pay for them is critical, as are tiered pricing schemes, donations, and other mechanisms that can ensure access to prevention, care, and treatment.
Recommendation D.3: By the end of 2016, the Pandemic Product Development Committee should convene regulatory agencies, industry stakeholders, and research organizations to:
- Commit to adopting research and development approaches during crises that maintain consistently high scientific standards.
- Define protocols and practical approaches to engage local scientists and community members in the conduct of research.
- Agree on ways to expedite medical product approval, manufacture, and distribution, including convergence of regulatory processes and standards; pre-approval of clinical trial designs; mechanisms for intellectual property management, data sharing and product liability; and approaches to vaccine manufacture, stockpiling, and distribution.
CLOSING REMARKS
It should be self-evident that scientific research must play a critical role in the global framework for countering the threat of infectious diseases. Yet to be able to react promptly to outbreaks with the potential to become pandemics by deploying new medicines, diagnostic tools, and instruments at pace, we need more R&D in this arena, and we need it to be better coordinated. To achieve this, the Commission recommends that WHO establish a dedicated entity, the PPDC, to define priorities, mobilize and allocate resources, and oversee progress. We recommend targeting incremental R&D spending of $1 billion per year, to be coordinated by the PPDC. This proposed budget does not include expenditures for AMR, although it is expected that innovative drugs supported by the PPDC may help address AMR. The Commission also recommends a number of actions to ensure that R&D during crises sustains the highest scientific standards, that communities are effectively engaged in R&D processes, and that many of the impediments to swift development, approval, and deployment of new medical products are tackled in advance.
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