One way to be prepared for potential, but as yet unknown, pandemic events is to create platforms that could be deployed in responding to a broad array of scenarios. Drawing from the workshop discussions, Yamada applied a standard pharmaceutical company value-chain model to the discussion of key issues in facilitating more rapid, efficient, and successful medical product research and development for pandemic preparedness. He summarized the key takeaway messages from the discussions in the form of a strategic analysis map, collating ideas for the development of platforms that would drive stakeholder investment (i.e., incentives); product discovery (basic research); development (including clinical research); regulatory expectations, review, and approval; and manufacturing, stockpiling, and distribution (see Table 7-1). Insights from panelists Kilmarx; Stoffels; Glenda Gray, President and CEO of the South Africa Medical Research Council; and Robin Robinson, Director of the Biomedical Advanced Research and Development Authority (BARDA), and comments from participants during an open discussion helped to complete the strategic analysis map and highlight priorities.
Yamada reiterated the concerns of many participants that there must be a process for prioritizing the diseases to be addressed first. The product discovery and development process is a long process, and it will be a disincentive to participate if the priority list changes every few years. Rex sug-
TABLE 7-1 Critical Considerations for Facilitating Medical Product Research and Development
- Trust: regular communication among stakeholders in advance of crisis
- Community Engagement: to gain trust and support for development (clinical trials), distribution, and compliance; sociological and anthropological research can help identify approaches to engaging communities
- Ethical and Legal Framework: agreed upon IP/data sharing and liability standards
- Leadership: strategies will differ in routine versus emergency operations. In an emergency, the designated global leadership group should establish priorities for products to develop, test, manufacture, and distribute, to ensure efficient use of limited time/resources
- Communication: accurate information about the emerging disease threat, diagnosis, prevention and control, and available treatments including ongoing clinical trials and how they work. Communication is key across all the crosscutting themes as well as throughout the R&D chain
- Barriers: eliminate unnecessary process/policy barriers, foster sustainability across the research and development spectrum
NOTES: This chart was presented by the workshop co-chairs at the workshop to highlight many of the main points of the workshop discussions and should not be construed as reflecting any group consensus. BARDA = U.S. Biomedical Advanced Research and Development Authority; BMGF = The Bill & Melinda Gates Foundation; BPO = biopreparedness organization; CDC = U.S. Centers for Disease Control and Prevention; GHIT = Global Health Innovative Technology Fund; GSK = GlaxoSmithKline; IP = intellectual property; MMV = Medicines for Malaria Venture; MRC = Medical Research Council; NGO = nongovernmental organization; NIH = U.S. National Institutes of Health; PPE = personal protective equipment; R&D = research and development; TB = tuberculosis.
SOURCE: Yamada and Freire summation of the workshop with input from participants during the final open discussion, August 21, 2015.
gested considering research priorities in four main categories: diagnostics, antibacterials, respiratory viruses, and nonrespiratory viruses. In splitting viral research into two categories, he explained that respiratory viruses have the potential for exponential spread that can cause public anxiety and paralyze the economy. Outterson highlighted the need for an inclusive global threat assessment that moves beyond the traditional silos (i.e., not just U.S.focused, bacteria-focused, virus-focused, etc.). Freire noted that BARDA1 has developed a list of priority diseases, and Bell suggested not only looking to the BARDA list as a starting point, but also looking at how the BARDA list was generated and considering whether a similar process for global diseases would be useful. Levine emphasized the need for constant surveillance for emerging pathogens to guide ongoing research and development. Kilmarx and Stoffels discussed the stratification of development priorities. For some products it might be critical to have a licensed product that is available and ready to launch. For others, the collection of preclinical data might be sufficient until the product is needed, at which point it would be ready for clinical trials. In the middle tier might be products for which phase I clinical trial data, and perhaps dose ranging studies, are desirable.
Pharmaceutical companies are motivated to participate, and are participating in many different ways, Yamada said. However, relying on self-driven research and development alone is not continuously dependable. One research incentive approach discussed was investments made by foundations and government in early, nontargeted research (sometimes referred to as “blue sky” funding). Public–private partnerships and product development partnerships were discussed as approaches to foster discovery and development, and the Japanese Global Health Innovative Technology Fund (GHIT) was reviewed as a model of how the public, private, and philanthropic sectors can come together to invest in products and technologies that advance health. Creatively structured prizes for product developers were discussed as a way to delink research and development costs from prices and revenues (similar to what has been done to foster the development of products to treat orphan diseases). The potential role of funding from insurance companies was also of interest, given that they factor risk into premiums. Marks observed that much of the discussion of incentives at
1 BARDA supports the development and procurement of drugs, vaccines, and other products that are considered priorities for U.S. national health security, including chemical, biological, radiological, and nuclear (CBRN) accidents, incidents and attacks, pandemic influenza, and emerging infectious diseases. See https://www.medicalcountermeasures.gov/barda.aspx (accessed November 13, 2015).
the workshop had related to companies that are already involved in product development for emerging threats, but incentives are also needed to encourage entry by those companies that are not yet engaged (i.e., to reduce the barriers to participation).
Critical elements of government participation, Yamada noted, are the recognition that a global health crisis is a national security concern, and the support of the security and economic or finance cabinet leaders for the inclusion of health in the national security agenda. Gray added that science drives good distribution practice (Jaffe et al., 2013), and until the countries on the African continent understand this and invest in research and development, they will not become wealthy. Yamada also noted that any government investments to spur development must be multiyear commitments.
Investment in discovery is needed across the spectrum of drugs, vaccines, diagnostics, and PPE. Yamada stressed that funding for academic research is critical. Research in academia expands the understanding of mechanisms of illness and pathophysiology of infection and identifies potential vaccine and therapeutic targets. Marks pointed out the need to align academic grant awards and government contracts with national and global health risk priorities. Many workshop participants discussed vaccine platforms that could potentially be U.S. Food and Drug Administration (FDA) preapproved for use. Promising vaccine platforms discussed included the seasonal influenza vaccine platform, nucleic acid–based vaccines (RNA-based vaccines, DNA plasmid vaccines, and live viral-vectored vaccines), and vectored delivery of immunogenic antigen (e.g., adeno-associated viruses [AAV] vectored). Examples of therapeutic platforms discussed included a novel mechanism to confer passive immunity using an AAV vector, and high-throughput screening of compound libraries and repurposing of existing compounds. Research is also needed for new devices, including diagnostics and personal protective equipment. Yamada and Pauwels noted that diagnostics for use in global health crises should be inexpensive, rapid, accurate, and available at the point of care. Kilmarx noted, however, that some of the current rapid diagnostics used at the point of care are not particularly sensitive, which is of concern for a screening test, especially in the case of false-negative results. Research on PPE is driven by both the way each infectious agent is transmitted, and the anticipated conditions of use.
Several participants, including Yamada and Levine, emphasized the importance of differentiating between clinical trial design for therapeutics
versus vaccines. For approval of a therapeutic product, many workshop participants stated that a randomized controlled clinical trial is preferred. There must be interpretable evidence of efficacy and safety relative to a comparator (e.g., existing standard of care, placebo), and that comparator should not be a historical control, Yamada observed. Cultural and practical hurdles to performing a randomized controlled trial were also cited, however, throughout the workshop discussions. For vaccines, there is more flexibility for creative or novel clinical trial designs. Among the examples discussed were the Ebola ring vaccine trial in close contacts of Ebola patients, in which one group of participants was vaccinated immediately after exposure to an infected person, while those in a second group were vaccinated 21 days after exposure.
Yamada noted that the amount of data needed before a pivotal trial can be initiated, and the extent to which data requirements could be adaptable to the urgency of the situation, are topics that need to be addressed. Yamada and Awunyo-Akaba also mentioned the need for immediate investment in clinical trial infrastructure and capacity building, before the next emergency. Also, given the many different products being developed, and the limited capacity to do the clinical trials, especially when a limited number of impacted patients or trial participants are available, there needs to be a designated person or entity who has authority to determine the priority of the proposed clinical trials.
The workshop discussions highlighted the ongoing advantages that harmonization of regulatory processes and regulatory science offer. The concept of preapproved clinical trial designs and protocols was raised and discussed by Yamada and Hamburg, as well as the possibility of preapproval of vaccine platforms.
An important, and potentially contentious, issue is the concept of division of or sharing of regulatory labor and resources for product review during an emergency. Specifically, would approval by one country be sufficient to allow use of the product in other countries? Kilmarx emphasized that overall coordination and cataloging of activities is needed to ensure meaningful action in the face of often limited clinical trial capacity.
Much of the discussion of manufacturing focused on the need to advance manufacturing technology. Yamada called for research on more rapid and efficient manufacturing processes, especially for vaccines. Another issue that was raised was the need for spare capacity and global capacity building,
both for the manufacturing and stockpiling of products, as well as spare pilot plant capacity for process development of investigational products. Models discussed included pharmaceutical manufacturers making portions of their capacity available, or creating a dedicated collaborative pilot manufacturing facility. Importantly, Yamada said, it is not just manufacturer capacity, but manufacturer knowhow and capability that need to be readily available. Yamada also emphasized concerns about countries nationalizing manufacturing capacity in times of crisis.
Distribution is a very complex process, Yamada said. Help is needed from people in country who know how to distribute in the area. In times of crisis, a broad base of support is needed, and additional assistance can come from the military, community, nongovernmental organizations, and other industries with last-mile delivery capabilities and expertise (Yamada suggested Amazon, Coca Cola, and FedEx as examples). Participants emphasized the critical role of accurate demand forecasting for successful distribution. The need for affordable pricing, particularly in regions such as Africa where prices of medical products are often set higher than in other countries, in part due to lower demand for products, was highlighted by Gray. There was also a call for attention to the ethical allocation of products. There is often misalignment between those who can pay and those at the greatest risk or with the greatest need. A global consensus for an ethical distribution construct is needed to ensure that the right drug is delivered to the right place at the right time, Yamada said.
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