Integrating Clinical Research into Epidemic Response The Ebola Experience (2017) / Chapter Skim
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. However, because all Ebola outbreaks prior to that in West Africa in 2014–2015 were relatively isolated and of short duration, little was known about how to best manage patients to improve survival, and there were no approved therapeutics or vaccines.
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The WHO declared the epidemic a public health emergency of international concern on August 8, 2014, and shortly thereafter researchers and stakeholders began discussing whether and how to conduct clinical trials on potential Ebola therapeutics and vaccines; these discussions ultimately resulted in several teams conducting formal clinical trials in the Ebola affected countries during the outbreak. In October 2015, the National Academies of Sciences, Engineering, and Medicine (the National Academies)
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(See Appendix A for more information on methodology.) ASSESSMENT OF EBOLA CLINICAL TRIALS The clinical trials that took place during the 2014–2015 Ebola epidemic were conducted in an atmosphere and on a timeline entirely different from most clinical trials.
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controls with results guiding subsequent trial design • Nonrandom, open-label • Single-arm, historical controls TKM-130803 • Multistage trial design Early results from the study, with boundaries based on demonstrated that TKM-130803 historical/contemporary was not effective in increasing controls with results the survival fraction above 50 guiding subsequent trial percent; unlikely to demonstrate design an overall therapeutic benefit to • Nonrandom, open-label patients. • Single-arm, historical controls ZMapp • Randomized, open-label ZMapp showed promise as • Two arms: ZMapp + a possible effective treatment optimized standard of agent for EVD, but there were care (oSOC)
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double-blind, placebo-controlled When the final immunogenicity • 2 treatment arms -- data become available, the results randomized 1:1:1 of the PREVAIL trial will provide to ChAd3-EBO-Z, information on the long-term VSVDG-ZEBOV, or immunogenicity of the vaccines, saline placebo including the one used in the ring vaccination study. ChAd3-EBOZ Trial – NIH PREVAIL Vaccine was well tolerated.
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On the other hand, humanitarian organizations providing care in the treatment units were skeptical of activities that drew effort away from their mission of providing clinical care to the most people possible. Properly designed clinical research is essential for answering questions about disease processes and for evaluating the safety and efficacy of potential therapeutics and vaccines; indeed, for diseases such as Ebola, an outbreak or epidemic presents the only opportunity to conduct such research.
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Randomized controlled trials (RCTs) are the preferred research design because they allow researchers to directly compare the outcomes of similar groups of people who differ only in the presence or absence of the investigational agent.
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For a disease like Ebola, where experimental human infections cannot be used to facilitate the conduct of clinical trials of investigational products, an outbreak provides the only opportunity to assess the efficacy of drug candidates in patients and assess the protection capability of vaccines. Strengthening Capacity The three countries most affected by the Ebola epidemic -- Guinea, Liberia, and Sierra Leone -- were among the countries that were perhaps the least equipped to respond to an epidemic or to support clinical research during an epidemic.
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The shortage of workers hindered the countries' ability to care for patients and to implement infection control measures, especially in the setting of containment and the need to wear personal protective equipment, and to collect patient-level data that could be used to inform treatment protocols in real time. The committee concluded that, while recognizing the challenges of collecting and recording patient data, it is critical to do so in order to document the natural history of the evolving epidemic and to provide clues to better patient management.
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to develop memoranda of understanding during the inter epidemic period to improve capacity to collect and share clinical data, with all necessary provisions to protect the privacy of individuals and anonymize data for epidemiological research. Recommendation 2b Provide resources to enable data collection and sharing -- Epidemic At the start of an outbreak, developed countries, research funders, and sponsors should work together with national and international health care providers responding to an outbreak, to provide the additional resources and personnel needed to enable systematic data collection on routine care practices and outcomes.
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• Develop template clinical trial agreements reflecting shared under standings about key issues such as data sharing, post-trial access to interventions, storage and analysis of biospecimens, and invest ments to build local capacity. In addition to the potential sources of experts in ethical review and the negotiation of clinical trial and material transfer agreements within schools of medicine and public health with extensive experience conducting clinical trials in low-resource settings, the nongovernmental organization Public Interest Intellectual Property Advisors, which provides pro bono legal advice to low- and middle-income countries regarding health research and contracts, and the Council on Health Research for Development, through its program on Fair Research Contracting, can be engaged to assist in these efforts, but will themselves require funding resources to participate.
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Recommendation 5 Enable the incorporation of research into national health systems -- Inter-epidemic National governments should strengthen and incorporate research systems into their emergency preparedness and response systems for epidemic infectious diseases. The multilateral institutions (the World Health Organization [WHO]
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Initial response efforts tended to be top down and did not take into account community traditions and beliefs -- for example, mandatory cremation policies countered deeply held religious beliefs. Over the course of the epidemic, communication and community engagement improved, and this resulted in an improved acceptance of and participation in infection control and research efforts.
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There are no events for which this is more applicable than emerging infectious disease outbreaks, for even when they are in the beginning apparently localized, they can quickly become globalized. During the Ebola epidemic, research and response efforts were greatly affected by the relationships between international stakeholders and their ability to coordinate and collaborate.
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Therefore, making progress on the R&D of products -- including therapeutics, vaccines, assays, and diagnostic tests -- during the inter-epidemic period is the only way to ensure that promising candidates are ready for trials once an outbreak occurs. To this end, the committee recommends that an international coalition of stakeholders work during the inter-epidemic period to advise on and invest in priority pathogens to target for R&D, develop generic clinical trial design templates, and identify teams of clinical research experts who could be deployed to assist with research during an outbreak.
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Recommendation 7b Establish and implement a cooperative international clinical research agenda -- Epidemic In the event of an emerging epidemic the international coalition of stakeholders (in Recommendation 7a) should designate an independent multistakeholder rapid research response workgroup with expertise in the pathogen of concern, research and development of investigational interventions, clinical trial design, and ethics and regulatory review, and including representatives from the affected communities, to 1.
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FIGURE S-1 A timeline of critical components: Launching clinical trials in an epidemic.
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The goal is to encourage an open dialogue among all relevant stakeholders to achieve a better understanding of the nature of the crisis, each stakeholders' interests, and resources available for addressing the epidemic, inclusive of the potential for research in the response. BEING PREPARED: LAUNCHING CLINICAL TRIALS IN AN EPIDEMIC Through targeted exploration and analysis of scientific and ethical issues related to clinical trial design, conduct, and reporting during the 2014–2015 Ebola epidemic in West Africa, the committee learned key lessons that could be applied to future research conducted in settings where there is limited health care and research infrastructure.
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