Vaccines and Global Health: The Week in Review has expanded its coverage of new reports, books, research and analysis published independent of the journal channel covered in Journal Watch below. Our interests span immunization and vaccines, as well as global public health, health governance, and associated themes. If you would like to suggest content to be included in this service, please contact David Curry at: firstname.lastname@example.org
Integrating Clinical Research into Epidemic Response: The Ebola Experience (2017)
Consensus Study Report
National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Global Health; Board on Health Sciences Policy; Committee on Clinical Trials During the 2014-2015 Ebola Outbreak; Gerald Keusch, Keith McAdam, Patricia Cuff, Michelle Mancher, and Emily R. Busta, Editors
June 2017 :: 310 pages
The 2014–2015 Ebola epidemic in western Africa was the longest and most deadly Ebola epidemic in history, resulting in 28,616 cases and 11,310 deaths in Guinea, Liberia, and Sierra Leone. The Ebola virus has been known since 1976, when two separate outbreaks were identified in the Democratic Republic of Congo (then Zaire) and South Sudan (then Sudan). 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. When the World Heath Organization declared the 2014-2015 epidemic a public health emergency of international concern in August 2014, several teams began conducting formal clinical trials in the Ebola affected countries during the outbreak.
Integrating Clinical Research into Epidemic Response: The Ebola Experience assesses the value of the clinical trials held during the 2014–2015 epidemic and makes recommendations about how the conduct of trials could be improved in the context of a future international emerging or re-emerging infectious disease events.
Jun 24, 2017 Volume 389 Number 10088 p2443-2586 e16
Clinical trials during epidemics
Gerald T Keusch, Keith P W J McAdam
The consensus report of the US National Academies of Sciences, Engineering and Medicine for the first time evaluates the clinical trials on Ebola therapeutics and vaccines in Guinea, Sierra Leone, and Liberia during 2014–15.1 The report presents seven recommendations for both interepidemic and epidemic periods to improve the likelihood that important new information on therapeutics and vaccines can be obtained during future epidemics. This information is especially critical for infections such as Ebola virus disease because the only time efficacy and safety of drugs or vaccines can be studied in infected or at-risk human beings is during an outbreak. The recommendations are based on analysis of what happened in west Africa, and fall into three main categories: capacity strengthening, engaging communities, and international coordination and collaboration.
Strengthening capacity in countries at risk of emerging epidemics to respond more effectively to outbreaks and evaluate unproven new drugs and vaccines seems obvious. Planning of trials should begin when effective outbreak surveillance and reporting identify an outbreak in progress, as mandated by the International Health Regulations of 2005.2 Although WHO is responsible for assuring the latter core competencies are achieved, without international experts and sufficient available donor funding WHO cannot meet its obligations. To be both effective and efficient, clinical trials research expertise must involve not only training researchers, but also integrating research within a health-care system, improving infrastructure for competent scientific and ethical review of human subject research, and establishing the capability to negotiate legal documents with trial sponsors.
The local health-care system in Guinea recognised and reported an unusual cluster of rapidly fatal illness in the Forestière region by mid-January, 2014, but the Ministry of Health was unable to identify the actual cause. Another 8 weeks elapsed before Ebola was confirmed, during which time the outbreak grew and spread to two additional countries and multiple urban centres.3 In the scramble to respond to meet basic care needs and halt transmission, the possibility to assess experimental drugs and vaccines received little attention until 5 months later when WHO declared a public health emergency of international concern.4 Despite herculean efforts to build necessary infrastructure and launch trials in record time, limited local experience with clinical research and poor capacity for timely scientific and ethical review or negotiation of research contracts, together with differing views of trial design and probable community reaction among local and international stakeholders, slowed the process.5
Unfortunately, record time was not fast enough: the nine formal clinical trials the committee evaluated all began as the outbreak was waning. The report describes the consequence as a “thin scientific harvest”,1 and 2 years later no licenced product is available. Strengthening the many areas of expertise required for clinical trials takes sustained effort, time, and funding before an outbreak strikes. The report concludes that the choice is to “pay now and prepare in advance, or to pay later when an outbreak occurs, with the likelihood that the cost will be multiple times greater”.1
Engaging local communities emerged as a complementary concern. Clinical trials require volunteers to participate, but in the context of an uncontrolled outbreak patients may not only be ill and inadequately informed, but also fearful, vulnerable, stigmatised, and confused about goals, benefits, and risks of trials. The relationship between researcher and participant, which depends on mutual trust, was difficult to achieve in west Africa, a region haunted by the memory of civil wars and ongoing distrust of authority, compounded by limited understanding among international researchers of local culture and social traditions.6 In the absence of trust, misunderstanding was the norm and resistance was the early response in affected communities. Building trusting relationships requires time and expertise in social science and communication.7 Despite early controversies about the ethics of doing trials during an emergency and assumptions that randomised controlled trials were unacceptable, and therefore nobody would volunteer,8 once community leaders and the community itself were effectively engaged, randomised controlled trials were successfully implemented.6, 9 The research community must learn how to accomplish this engagement more efficiently in the future.
International coordination and cooperation are essential to avoid the conflict and competition that will inevitably arise again when the next outbreak occurs. This coordination requires pre-emptive joint efforts among international and national stakeholders, including the humanitarian response, research and development, and clinical trials communities, to integrate research into response, have therapeutic and vaccine candidates ready to go, and agree on principles and processes to speed priority setting, and design, approval, and implementation of clinical trials. The report recommends such efforts be led by a Coalition of International Stakeholders, which is purpose-built, independent, free of conflicts of interest, possesses expertise in many disciplines, and includes representation from governments, WHO, academia, the private sector, humanitarian response organisations, and the countries and communities at risk. The coalition would need secure financial resources to lead the effort to establish necessary global mechanisms and commitments. It should have the responsibility and resources to convene an expert, independent Rapid Research Response Workgroup at the outset of a new outbreak, including national and community participants from affected countries, to prioritise which candidates to study, determine appropriate trial design, and facilitate implementation. The report concludes: “If national and international researchers can work together on a collaborative and coordinated research agenda, and include input from the population at risk, the global community has the best chance at being prepared for the next outbreak.”1 The time to act on these recommendations is now.
The next step is to engage the many stakeholders across continents, including WHO, the World Bank, UN system, governments, research-funding agencies and foundations, academic institutions, humanitarian and civil society organisations, and others, in thoughtful discussion to determine the best way forward.
The US National Academies of Sciences, Engineering and Medicine and former members of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak are reaching out to key stakeholders to stimulate these efforts through presentations, publications, and personal contacts. Major questions remain to be resolved. How can we systematically integrate clinical and social science research expertise with emergency response? Can we create a tool box with model study designs for different outbreak scenarios, pathways for community engagement, tutorials on ethical guidelines, and more, and provide training for future leaders in countries at particular risk for emerging infections in their use, and so speed action when an epidemic begins? What is the best governance model and the particular role of WHO? Who will take leadership and where will the funds and political will come from? The answers to these questions will guide these efforts to refresh the necessary collaborative global leadership, help it to thrive, and ensure it is held to account.
We were Co-Chairs of the US National Academies of Sciences, Engineering, and Medicine’s Committee on Clinical Trials During the 2014–2015 Ebola Outbreak. We declare no other competing interests.
The other members of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak were: Abdel Babiker, Mohamed Bailor Barrie, Janice Cooper, Sheila Davis, Kathryn Edwards, Susan Ellenberg, Roger Lewis, Alex John London, Jens Lundgren, Michelle Mello, Olayemi Omotade, David Peters, Fred Wabwire-Mangen, and Charles Wells. National Academies of Sciences, Engineering, and Medicine study staff were: Patricia Cuff, Michelle Mancher, Emily Busta, Michael Berrios, Anne Claiborne, Julie Pavlin, and Andrew Pope.
US National Academies of Sciences, Engineering and Medicine. ((accessed June 12, 2017).)Committee on Clinical Trials During the 2014–2015 Ebola Outbreak. Integrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC; 2017