Development encompasses the process of bringing a candidate identified in the discovery research phase to market and generally spans preclinical testing, clinical assessment, and regulatory approval. Much of the discussion of development at the workshop focused on the design and conduct of clinical trials during a public health crisis. Participants also discussed the importance of engaging affected communities as stakeholders and partners in the development process (regulatory issues are discussed in the following section). Highlights and main points are summarized in the box below.
Highlights and Main Points Made by Individual Speakers and Participantsa
- The importance of distinguishing between trials of vaccines and those of therapeutics when discussing trial design was emphasized, as the immunogenic mechanisms of vaccines are different from the therapeutic mechanisms of action of drugs. However, scientific rigor is a key component in both. (Binka, Kalil, Rex)
- Regulatory entities need to see interpretable data. From an ethics perspective, no study should be undertaken unless the results will be interpretable. (Borio, Califf, Kalil)
- The core issue for robust clinical trial design is appropriate controls or comparators.
- For trials of therapeutic products, a randomized controlled trial is most rigorous. The appropriate control is usually the standard medical care for the condition (although, for emerging diseases, the only option might be supportive care). (Borio, Kalil, Kilmarx, Levine)
- For vaccine trials, there could be more flexibility for novel clinical trial designs (e.g., the Ebola ring vaccination trial with the 21-day vaccination delay control group). (Borio, Levine)
- Historical controls are unreliable and do not represent what is currently happening in the field. Studies comparing two investigational products can be misleading. (Borio, Kalil, Kilmarx)
- Adaptive clinical trial design and analysis could be helpful, including the use of traditional (frequentist) and Bayesian statistical methods. Adaptive randomized trial design can allow for multiple interventions (perhaps from multiple manufacturers) to be evaluated against one shared control group, resulting in greater efficiency and fewer participants receiving the standard of care control intervention. (Borio, Kalil, Kilmarx)
- Participants acknowledged that during the Ebola outbreak many decisions regarding optimal trial designs were made quickly and under challenging circumstances. Participants also discussed the need for more sustained communication among governments, researchers, nongovernmental organizations (NGOs), and communities to better align and be more prepared for future outbreaks. (Binka, Califf, Lee)
- Participants acknowledged the challenges of clinical trials in the face of extremely limited infrastructure and inadequate capacity and discussed the need to consider studies in the context of the reality on the ground. (Kilmarx, Levine)
- It is important that clinical studies be acceptable to the affected populations. Engaging the community, including all community leaders, is key for success. Educate the public about the disease, the dynamics of epidemics and prevention, and clinical trials. Fight fear with facts, in local languages with meaningful messages. The most effective communication is two-directional, with feedback from the community informing policy, practice, and service delivery. (Awunyo-Akaba, Bell, Binka, Borio, Califf, Hall, Kilmarx, Sow, Yamada)
- Infrastructure and capacity building across the areas of physical infrastructure, human resources, laboratory capacity and quality assurance, data management capacity, systems of ethical review, and training (including ethical reviewers, NGO leadership, and others) are important. (Awunyo-Akaba, Bell, Binka, Kilmarx)
a This list is the rapporteurs’ summary of the main points made by individual speakers and participants and does not reflect any consensus among workshop participants.
Design and Conduct of Clinical Trials During a Public Health Crisis
During the 2014-2015 Ebola outbreak, the global scientific community organized and made progress on identifying and accelerating progress of promising vaccines and therapeutic interventions, since none had yet been approved (Adebamowo et al., 2014). Many of these interventions had never been tested in humans and so, over the course of the response, a global debate ensued over how to best assess the clinical safety and effectiveness of novel interventions during the public health crisis (Adebamowo et al., 2014; Cox et al., 2014). Some in the scientific and medical communities believed that the situation on the ground made the prospect of conducting randomized controlled trials (RCTs) untenable from a practical perspective, and that alternative study designs that could be implemented more rapidly needed to be pursued (Adebamowo et al., 2014). Others contended that randomization with controls is fundamental to collecting reliable data on the safety and efficacy of novel products and must be preserved (Cox et al., 2014). The presentations and discussions at the workshop articulated these different perspectives. Discussion focused on the methodological design considerations for both vaccine and therapeutic clinical trials and the practical challenges encountered by those conducting trials in West Africa during that time.
In his presentation, Andre Kalil, Director of the Transplant ID Program at the University of Nebraska Medical Center, noted that the most optimal and ethical study design for evaluating experimental drugs with low availability, in diseases affecting low-resource areas, is the one that offers the highest probability of detecting true success or true failure with the
experimental drug. The study design with the most robust methodology and the highest probability of detecting the effect of an experimental drug and distinguishing true signal from noise (e.g., patient selection bias, confounding, and chance) is the RCT, he continued. He remarked that no other study design offers a higher benefit–risk ratio with the most treatment equipoise to all patients, better utilizes the limited availability of experimental drugs, evaluates the efficacy of experimental drugs in a timely fashion for the benefit of those impacted today, or accrues as valid and reliable results for the benefit of all patients now and in the future.
Kalil listed and refuted some of the arguments made against randomized controlled trials in the context of the Ebola outbreak. A key argument made was that patients and health care professionals in Africa would not accept randomization because Ebola mortality is so high. Kalil countered that RCTs for acute illnesses with very high mortality are done every day all over the world to evaluate new therapies (e.g., septic shock hospital-acquired infections, encephalitis, and necrotizing fasciitis). Another argument made was that patients and health care professionals in Africa would not consent to having a random chance to receive either the investigational drug or the control. In reality, Kalil said, randomized trials for acute and chronic illness have been performed with an appropriate consent process in tens of thousands of patients in Africa, for a multitude of diseases (e.g., severe sepsis, tuberculosis, malaria, HIV, and meningitis). It has also been argued that observational trials can be done faster than randomized trials. In fact, Kalil said, RCTs can be done quickly, especially with adaptive, Bayesian, and sequential group analysis designs. Several experimental therapies can be tested in a timely fashion, and new participants can be added to more promising intervention arms as data are collected, with a potential overall result that fewer patients are unnecessarily exposed to an ineffective or harmful drug, while more patients are exposed to effective or beneficial drugs during the trial. It is also not the case, Kalil said, that randomized trials are more expensive. For a new experimental drug, he noted, randomized designs are actually less costly and require fewer resources than other designs because the information gathered will bring at once (instead of from multiple observational studies) a more definitive (less biased) result regarding the drug’s efficacy. Moreover, the addition of an adaptive Bayesian design makes randomized trials even more cost effective. Another argument is that randomized studies are unnecessary if a drug has demonstrated very high survival success in small animals and nonhuman primate models. Kalil cautioned that medical history is full of experience with prospective drugs that showed impressive benefits in animals models but failed in randomized human studies (e.g., a variety of monoclonal and polyclonal antibody therapies).
Kalil also stressed the dangers of using a historical control rather
than concurrent controls, stating that historical controls do not necessarily reflect what is happening in the field. Factors such as disease severity and supportive care change from facility to facility in the same area, from country to country, and over time. Kalil then described an ongoing multicenter, randomized safety and efficacy study of Ebola treatment sponsored by a National Institutes of Health (NIH) trial (NCT02363322).1 The study is being done at a variety of sites around the United States and in Guinea, Liberia, and Sierra Leone, and employs an adaptive study design.
Kalil raised concerns that, through small uncontrolled single-arm studies being done in Africa, patients are being exposed to lower-quality study designs with low probability to produce interpretable valid replicable results. Kalil proposed that, unless an infectious disease outbreak is associated with 100 percent mortality, no single-arm trials should be initiated in a country due to the following reasons: high likelihood to produce uninterpretable and uninformative results, high likelihood to produce biased and not-replicable results, and results too uncertain to be applied during the outbreak, so they would not benefit current patients or change the course of the outbreak and would further deplete the availability of experimental drugs for RCTs. From a business perspective, a drug could be found falsely ineffective or unsafe, or falsely effective or safe, for reasons unrelated to the drug.
Peter Kilmarx, Deputy Director of the Fogarty International Center at NIH, elaborated on the challenges of clinical trials in the face of extremely limited infrastructure and inadequate capacity (e.g., limited physical infrastructure and human resources; lack of training; lack of laboratory capacity, systems, and quality assurance; lack of data management capacity and data; and lack of systems of ethical review). A controlled clinical assessment should generally be done for any novel treatment or pathogen, Kilmarx said, acknowledging that there are some exceptions (e.g., seasonal influenza vaccine, and possible compassionate use of promising interventions when there are too few cases to conduct a clinical trial). The most appropriate clinical trial design, from the NIH standpoint, is the randomized placebo-controlled double-blinded trial. Kilmarx concurred with Kalil that this generates the most robust data in terms of safety and efficacy of the product, as well as duration of protection for vaccines. He also agreed that declining incidence makes it inappropriate to use historical controls for a vaccine or prevention study. Kilmarx said the use of peramivir under an emergency use authorization (EUA) during the 2009 H1N1 pandemic underscores the importance of the randomized controlled clinical trial. Although there were attempts to capture data during use of the product, the data derived from this uncontrolled use were not reliable or interpretable (Borio et al., 2015).
Subsequent clinical trials showed no benefit or harm from the treatment (despite suggestion during the use under EUA that there was increased mortality).
Kilmarx briefly reviewed the NIH adaptive randomized trial design, which allows for multiple interventions to be evaluated against one shared control group, resulting in greater efficiency and fewer participants receiving the standard-of-care control intervention. Interim analysis and early stopping points allow for the discontinuation of trial arms where there is demonstrated toxicity or lack of efficacy (Borio et al., 2015). This model was the basis for the Partnership for Research on Ebola Virus in Liberia 2 study.2
Nancy Lee, Senior Policy Advisor at Wellcome Trust (WT), countered that in the case of the recent Ebola outbreak in West Africa, circumstances on the ground, including lack of trust by the people, lack of government cooperation, and serious time and resource constraints, led to the determination that RCTs were not feasible and alternative designs needed to be considered. She stated that WT’s priorities were to achieve (1) rapid results, (2) ethically appropriate implementation, and (3) interpretable data. Considering those priorities, she said, they believed that they needed to look into an alternative to the RCT and decided to first conduct single-arm studies, to collect as much information as possible on the novel therapeutics. Dull noted that The Bill & Melinda Gates Foundation (BMGF) considered single-arm or observational studies to be a step in part of a larger study group that led to RCTs as well. Dull contended that observational studies could be useful in that context and especially for identifying highly efficacious or kill products.
Myron Levine, Associate Dean for Global Health, Vaccinology, and Infectious Diseases at the University of Maryland School of Medicine, offered another perspective on ways of conducting clinical trials in a crisis, calling for more flexibility in trial design. With regard to the need for randomized studies of treatments, Levine agreed with Kalil but added that one must consider studies in the context of the reality on the ground. Levine’s opinion diverged somewhat with regard to vaccine trials, for which he said much wider possibilities are needed. Historically, he said, there has been licensure of vaccines that have proven to be critical public health tools without classical randomized controlled trials (e.g., the Haemophilus influenzae Type b [Hib] conjugate vaccine, part of the vaccine preparations that the United Nations Children’s Fund [UNICEF] gives out to developing countries, was licensed on the basis of serological noninferiority to two
2 For more information on the study see http://www.niaid.nih.gov/news/newsreleases/2015/Pages/ZMapp.aspx (accessed October 30, 2015).
other polysaccharide conjugate vaccines which had been evaluated in classic randomized controlled double-blind studies).
Levine described the very rapid development of two existing Ebola vaccine candidates, the chimpanzee adenovirus-3 vectored vaccine (ChAd3) and the vesicular stomatitis virus–vectored Ebola vaccine. Ethical Review Committees, regulatory agencies, funders, and most political authorities partnered in the highly accelerated timeline for phase I trials, final dosage levels were rapidly selected, less stringent cold chain conditions were worked out, and large-scale phase III trials were planned or initiated based on phase I/II results. Levine posed the questions of whether these studies could have been done even faster, and asked whether this experience could be repeated. The Guinea ring vaccination trial, Levine explained, was a novel randomized trial design where all participants received vaccine. Following identification and confirmation of a case of Ebola by the public health service, contacts received immediate vaccination or vaccine after a 21-day delay. That 21-day delay, he said, afforded biostatisticians the ability to compare the difference if one started counting cases 10 days after the ring vaccination began. Levine suggested that licensure of one or more Ebola vaccines based on nonhuman primate protection results and human safety and immunogenicity data from accelerated phase I and II trials could have allowed field effectiveness to be studied through less complex post-licensure designs (Levine et al., 2015).
Participants shared many opinions on the merits and limitations of the clinical trials conducted during the Ebola outbreak. It was suggested, for example, that the ring vaccination strategy in Guinea was fortuitous as it provided short-lived but high-level protection for those at high risk. A trial designed to randomly allocate vaccine to the general population would likely have had a much lower demonstration of efficacy, and perhaps not even reached its end points. Freire noted that the Foundation for the NIH, with funding from BMGF, has hired McKinsey to do a comprehensive study of the clinical landscape during the Ebola crisis. It is expected that the results will be housed on the World Health Organization (WHO) website and would be publicly available for study.
Participants discussed at length the benefits and limitations of the different approaches to clinical trials in a crisis situation. Rex emphasized the need to distinguish between trials of vaccines and those of therapeutics when discussing trial design, but, in either case, scientific rigor is essential, he said. Borio reiterated that the core issue for clinical trial design is appropriate controls, and there are many ways to establish an appropriate control for vaccine studies. For therapeutic trials of emerging infectious diseases, options are limited, despite our best creative efforts, Borio said, and historical controls are simply unreliable, she reiterated. The best approach for therapeutics would be to use Bayesian designs and adaptive clinical trials.
Participants discussed the elements of adaptive clinical trial designs, including the use of traditional (frequentist) and Bayesian statistical methods in adaptive trial design and analysis.3 Califf summarized that one size does not fit all. He observed that many of the decisions made relate to how affected populations perceive what is being done to them, and how governments react. The concept of randomization is not well understood, and more education of the public and researchers about the value and implication of randomization is needed.
Dull relayed that, in the chaotic setting of the Ebola pandemic, it was extremely challenging to work with development partners that had never run clinical trials before, and to conduct clinical trials of a product that had not yet entered into phase I testing. He noted that BMGF has worked to develop platform-based clinical trials that investigators could “plug and play” different products into, and has engaged in discussions with the U.S. Food and Drug Administration (FDA) about having study protocols in place so that a trial can be launched much more quickly in the event of an outbreak.
Bilbe suggested that one approach to meeting extremely short time frames for product delivery in a crisis is to repurpose drugs from other settings. He noted that the Drugs for Neglected Diseases initiative (DNDi) grew out of a recognition by Médecins Sans Frontières (MSF, Doctors Without Borders) of the lack of needed medicines in the developing world. In a pandemic setting, when a disease is emerging and may be yet unknown, one approach is to study the course of disease while the patient is being treated. Bilbe observed, however, that MSF was so overloaded with the avalanche of patients during the Ebola outbreak that data simply could not be collected as part of the treatment process. This is a major drawback in terms of learning about the usefulness of drugs being administered in that setting, he said. Spigelman added that MSF treats more multidrug-resistant tuberculosis patients than any other single entity, and yet there has been no prospective data coming out of that resource.
3 FDA guidance states that “an adaptive design clinical study is defined as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned timepoints within the study, can be performed in a fully blinded manner or in an unblinded manner, and can occur with or without formal statistical hypothesis testing.” See Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics at http://www.fda.gov/downloads/drugs/guidancecomplian-%20ceregulatoryinformation/guidances/ucm201790.pdf (accessed October 30, 2015).
Fred Binka, Vice Chancellor at the University of Health Allied Sciences in Ghana, said that ethics is a major pillar of clinical research, and, simply, if the trial design is not good, it is not ethical. National ethics policies in Africa are often driven by requirements from external funders. With the exceptions of Malawi, Senegal, South Africa, and Tanzania, most countries in Africa have not enacted laws to regulate research ethics. Modalities for ethical reviews are varied (e.g., whether fees are charged, and if there is funding from central government). There were major efforts to try to improve ethical reviews of clinical research in Africa, and several African associations were developed (e.g., the Pan-African Bioethics Initiative), but Binka noted that efforts have waned in the absence of resources. Currently, there are 170 research ethics committees in various stages of maturity, but most countries do not have a national ethics committee. Committees are generally within institutions and, while membership is adequate, the committees are not well supported or well trained. There are large volumes of protocols for review, and attrition rates for the volunteer committee members are high. Funding for ethics committees is variable, with most now charging fees because support from their governments is not adequate.
Binka noted that the African Vaccine Regulatory Forum (AVAREF) is pursuing regulatory reform. This group, established in 2007, is a platform for information sharing by product developers on vaccine candidates, target countries, and timelines for clinical trials. It fosters communication and collaboration among the national regulatory authorities and ethics committees in most countries and provides expertise to regulators in support of the review process. Twenty-two countries are now members of AVAREF, and Binka called for development at the African Union level and the creation of an African Regulatory Agency. Support from stakeholders is needed to develop research ethics capacity in Africa through AVAREF, and for training in specialized areas (e.g., novel designs, genetic studies, and tissue storage for long-term use), he said. The goal, he concluded, should be the formation of national ethics committees with appropriate funding to protect participants in research.
Stoffels said that, in addition to designing the best study within the range of possibilities, it is also essential to give confidence to African communities that they will have first access to the product being tested once it is approved (i.e., that they are not simply being used as a test population).
Rob Califf, Deputy Commissioner for Medical Products and Tobacco at FDA, echoed the comments of other speakers that making clinical deci-
sions without robust evidence is bad social, cultural, and health policy. Califf agreed that the classical randomized clinical trial is the method of choice where possible, but he pointed out that many trials being done in some fields now have a single arm (e.g., oncology trials). Hans-Georg Eichler, Senior Medical Officer at the European Medicines Agency (EMA), agreed that there are new oncology and orphan drug products authorized in the United States and European Union (EU) that have not been tested in an RCT. He called for flexibility in using the entire spectrum of evaluation methodologies available, and not restricting development to RCTs only. However, some participants, including Kalil and Borio, cautioned that oncology trials and acute infectious disease trials are different in that most of the oncology single-arm trials are for cancers with 100 percent mortality, and the trial participants have generally already exhausted all other chemotherapy options. Moreover, the disease processes for cancer and for acute infectious diseases are very different.
Borio said that FDA needs to see interpretable data coming out of clinical studies, and generally speaking, that means randomized trials where the test product is evaluated against an appropriate control. These types of trials can take many shapes and forms. Trials of vaccines could be, for example, a classic RCT (as was done in Liberia) or a trial comparing outcomes in those that receive immediate versus delayed vaccination (as was done in Sierra Leone). Trials to test vaccines may have an added flexibility, she said, in that a clinical end point is desirable, but not always required. Vaccines could also be evaluated based on immunogenicity studies (demonstrating production of protective antibodies). FDA is committed to embracing scientifically sound innovation, Borio said, noting the example of using Bayesian analytical techniques to guide trial design.
For trials of therapeutic products to lead to interpretable data, the product must be compared to an appropriate control, which is usually the standard medical care for the condition (often a preexisting therapy), she said. Borio noted that for emerging infectious diseases for which there is no specific therapy, supportive treatment might be the standard-of-care comparator (e.g., intravenous fluids for electrolyte replacement and hemodynamic support). She stressed that studies comparing two investigational products can be misleading. For example, comparing what might be a relatively safe but ineffective product to a toxic product could give the illusion that the safe but ineffective product was actually helpful, which could lead to the adoption of the ineffective therapy and impede development of a truly effective product.
For a truly successful outcome, Borio concluded, clinical studies need to be feasible, ethical, scientifically valid, and acceptable to the affected populations. Borio reminded participants that clinical trial outcome is only
part of the licensing application; trials must be appropriately executed with integrity, and a quality product must be manufactured consistently.
Freire noted that, while academia has a critical role in basic research, to truly be a partner at the clinical trial level, there needs to be education on what it takes to conduct a trial that will generate the type of information needed for regulatory agency review.
Samba Sow, Director General of the Center for Vaccine Development–Mali (CVD–Mali),4 discussed practical considerations and community engagement in the context of the Ebola clinical trials conducted in Mali. Sow emphasized the importance of leadership, and of having field centers from which surveillance, monitoring, basic research, and clinical trials can be managed.
Sow highlighted some of the many practical challenges of conducting Ebola clinical trials in Mali. He relayed that the Ministry of Health required that the protocol be presented to all of the institutional review boards (IRBs) in the country, which amounted to three valid IRBs, only one of which, he said, was well trained. It was a very difficult process, in large part due to a lack of understanding of clinical trials and the concept of randomization. There are also complicated issues surrounding trial insurance and malpractice insurance. In Mali, after securing IRB approval and obtaining insurance, it is necessary to get an import permit, and then a formal authorization from the Ministry of Health. Only then can investigators begin to provide information to community leaders, local associations, traditional healers, and community members.
Sow summarized some of the other challenges as the speed of the recent Ebola crisis; the influx of partners, many of whom were focused on their own interests rather than those of the country; the lack of border control between countries; political instability; the safety and security of health workers; funeral practices (where cultural ceremonies include washing of the body, touching the deceased); a low literacy rate; religious beliefs (e.g., concerns that vaccines may contain material of pork origin such as gelatin); cultural beliefs, sensitivities, and myths (e.g., that vaccines cause sterility in women or infants); and the power and influence of traditional healers and
4 CVD–Mali was created in 2001 under an agreement between the University of Maryland Center for Vaccine Development and the Ministry of Health of Mali, and is administratively part of the Ministry of Health. The mission of CVD–Mali is to prevent, control, and treat endemic and epidemic infectious diseases in Mali and to train Malian specialists in vaccine-preventable infections, disease surveillance, and field research.
local doctors (many of whom were not knowledgeable about Ebola and its modes of transmission, and died in their efforts to treat patients). Sow noted that it is very difficult to talk about a double-blind RCT to people who have only known traditional medicine all of their lives.
Sow shared a harrowing account of his personal experience of Ebola’s arrival in Mali, when the Minister of Health asked him to see three men coming from Guinea with suspected cases of Ebola. His only protective equipment was a pair of gloves; one afflicted man fled the health center into the community and was not retrieved by police until 24 hours later; and the health center was surrounded by dozens of people who threatened the lives of Sow and the patients. They were relocated to a “safer” location, in an old meningitis epidemic quarantine facility infested with snakes. The government sent more than 100 heavily armed soldiers to surround his place of work where he tried to set up a treatment center, and also Sow’s home, where he ultimately decided to take the patients.
Any effort involving public health, including research, must start and end with the community, Sow said. One must understand the situation in the field, and Western textbook science and academic center trial designs do not apply necessarily to West Africa. In engaging members of the community it is important to recognize community values, beliefs, attitudes, and behaviors about vaccines or other treatments, clinical trials, and around research in general. Community knowledge and understanding of the disease is key, Sow said, noting that there was resistance to a proposed vaccine trial because there was no Ebola in Mali at the time. It was challenging to explain that the vaccine trial was important for prevention, not treatment. Education involves organizing meetings with local leaders and the community (before, during, and after), with assistance from the military or other security leaders. Involving all community leaders is important (including the traditional, religious, administrative, political, and sociocultural leaders). Researchers also need to understand the role of traditional healers and engage them. It is important to use simple, local, understandable language, to convey how the trial could directly and indirectly benefit participants and communities, to address issues of vulnerable groups, to discuss the results and impact of previous studies, and to highlight the experience of the investigators. Sow added that it is best to use experienced local investigators if possible. After getting community permission to proceed, individual consent or assent must be obtained from participants. Sow added that in Mali, the national language office translates the consent form into the local language, both in writing and to audiotape.
Awunyo-Akaba spoke from the civil society perspective. The global health risk framework is for the people, she said, country led but community owned. Building on the picture of Mali created by Sow, Awunyo-Akaba said Ghana has 10 regions, 225 districts, and 44,000 communities. The
communities are expected to take care of everything, from providing their own electricity poles and water, to building their own health compounds, and much more. There are no industries in those communities and most residents are subsistence farmers. The people of Ghana have myriad qualities, traditions, dynamics, values, and norms that cannot be violated. The traditional leaders in the villages are the source of authority and decision making, but they cannot make good decisions for their people without information. To be successful, a global risk framework must engage the community and community systems, including religious leaders, traditional leaders, and peer groups. She urged product developers also to keep the challenges for frontline workers on the ground in mind (e.g., terrain, temperature, and limited infrastructure). Cold chain storage, for example, is a significant challenge for a health worker that must travel an hour each way by public transportation to pick up a vaccine as well as wait an hour in the sun for the bus to come.
Civil society groups and local NGOs are willing to go to the communities because, Awunyo-Akaba said, they live with the people, speak their language, understand the nuances, and, in some cases, have earned their trust. However, local NGOs that have been able to reach communities are struggling without adequate funding or resources. NGOs and communities also need information. It is not enough to tell people not to touch each other, as some television advertising campaigns did. Tell them what is being done, she said, and tell them the truth. Awunyo-Akaba called for clear mechanisms for scientists to work with civil society and local NGOs, to build the capacity of NGO leadership, and to support NGOs in engaging the community and spreading information. She added that children are agents of change, and even in Ghana, they all know the popular characters from Western television and movies. She suggested that primers be created for children that teach the dynamics of epidemics and prevention in their own language, so that they grow up with this knowledge, and enhance it.
Binka described the reactions to a proposed Ebola vaccine trial in Ghana. The Ghana Academy of Arts and Sciences (GAAS) set up a committee to consider concerns about the trial, including a stated concern about a lack of clarity about who decides which vaccines should be tested in Ghana, the likelihood of “escape” of the virus into the community, and the likelihood that the vaccine would cause disease in humans. GAAS was also concerned that Ebola patients would need to be imported into Ghana for a phase II trial, as Ghana had no recorded cases of Ebola (though this was not the case as the trial was proposed to be conducted in healthy volunteers). These concerns, Binka said, “raised absolute panic.” A health NGO mounted a campaign, there were public demonstrations, and members of Parliament made statements, asking for the trials to be stopped. The Minister of Health was then summoned to Parliament to explain why these
trials were being done in the country. Ultimately, a statement was published announcing the suspension of the clinical trials, and the minister requested national public education on the trial. For 2 months, Binka traveled to four regions in Ghana, organizing local forums to educate the public on the phase I Ebola vaccine trial. Binka also met with the Parliamentary Subcommittee on Health, the Parliamentary Privileges Committee, GAAS, and many others. At the same time, there were numerous articles in the press, many quite sensational, discussing the proposed trial as well as the reactions of politicians and the public. A leading scientist who made a negative comment on the radio about Parliament stopping the clinical study was put on trial and ordered to publicly apologize.
It all comes down to communication, Binka said. Ultimately, the Paramount Chief in the region where the trial was to be done stated in an interview that he never had any concerns about the vaccine trial, because the researchers had met with all the traditional leaders in the municipality, and they felt well informed and were satisfied, long before the political “hullabaloo.”5 One positive outcome of the experience was that it created a forum for discussion and forged a bond between the Food and Drug Authority and investigators. Moving forward, Binka said, community engagement should start from day one. Actively engage and educate stakeholders, community groups, and journalists, and fight fear with facts. He added that moderation of public engagement events by WHO helps to provide assurance and legitimacy.
Beth Bell, Director of the National Center for Emerging and Zoonotic Infectious Diseases at the U.S. Centers for Disease Control and Prevention (CDC), echoed the comments by Sow and Awunyo-Akaba on the importance of civil society and social mobilization. Often, the most severely affected are also the most vulnerable. She said that it is essential to understand the local context of the outbreak and mobilize local partners in the community to help respond. Bell reminded participants that research conducted in the context of an outbreak must be done in coordination with public health, so that the research supports the outbreak response and does not interfere with public health efforts to control the outbreak. In addition, research capacity is connected to basic public health capacity, which is built on surveillance, early detection, and fundamental laboratory capacities, as well as training and response. The world now sees what happens when there is no infrastructure and no capacity, Bell said. Califf agreed that health care research capacity building is critical and that the same infrastructure is necessary for research on noncommunicable diseases that also affect populations in low-resource countries. We are going to have to be able to do trials that are relevant to the population there, he said.
Participants discussed further the issues of communication raised by Sow, Awunyo-Akaba, Binka, and Bell. The community response in the face of a need for public health interventions and clinical trials is an important component of success in interrupting transmission; however, health communication to facilitate a positive response is not always done well. It is important to listen carefully to what the community is saying, Bell said, and things that may seem small to nonlocal providers or researchers could be significant to the community. For example, by listening to the local population, CDC learned that the term “Ebola vaccine” led people to think that the vaccine would give them Ebola, and that saying “Ebola prevention vaccine” was more clearly understood and accepted.
Yamada suggested that many clinical trial participants who have given informed consent may not have really given educated consent. They have been informed of the risks and benefits but do not necessarily understand what the trial is about, or about clinical trials in general and that their purpose is to test new medicines that might not work as expected, and might cause harm. Yamada suggested a marketing approach to providing education, using words and messages that are meaningful to the target audience. Binka said that it is very difficult to explain in the consent process that these are investigational drugs and that the study is to prove whether they work or not. People commonly ask, if it does not work, why are you here to give it to people? Sow said that the concept of clinical studies is new in these parts of the world. He added that there are more than 150 languages in Mali, and not one of them has a good translation for “randomization,” so getting the message across can be very difficult. A participant said that, for some trials, a comprehension exam was given to participants as part of the consent process, to demonstrate their knowledge about, for example, the use of placebo, or their risk of infection. In Guinea, where there are 39 local languages, communication can also be very challenging. A participant noted that Sierra Leone has done several national knowledge, attitudes, and practices surveys to help inform a robust set of communication activities.
Awunyo-Akaba suggested developing clear fact sheets about preventable diseases, translated into local languages. Preventable diseases have been somewhat forgotten; for example, few frontline health workers have seen a case of diphtheria. Mothers know that their children have received all of their immunizations, but they do not actually know what the child was immunized against. Even the average NGO worker who works to create demand for immunization cannot explain the symptoms of these diseases and the basic actions to take if one of these diseases is suspected. Fact sheets would help to guide those who educate and interact with the
community (including the children, who are often called on to read and interpret for their illiterate parents).
Hall observed that communication and social mobilization in crisis situations such as the Ebola outbreak are often one-directional, with no feedback from the community. This is a huge problem, she said, because in many cases the community simply cannot take the action described in the information given (e.g., there may be no safe, trusted place to take people for isolation, and no burial teams to collect loved ones). The concept of one-way communication without matching service delivery is not likely to be successful, she said.