15. History, Culture, and Social Norms: Implications for Ebola Drug and Vaccine Clinical Trials

Morenike Oluwatoyin Folayan; Bridget Haire

The quantity of literature published during the months that followed the Ebola virus disease (EVD) outbreak in West Africa was unprecedented in the history of a disease identified almost 40 years ago. The magnitude of the outbreak in West Africa, which started in December 2013 and was on the decline as of July 2015,1 makes it clear that while countries in the “Ebola zone” have borne the brunt of the epidemic, the impact of the outbreak is global.

The EVD epidemic precipitated debates about the appropriate methodologies for conducting clinical trials of drugs and vaccines during a major infectious disease outbreak. Urgency regarding drug development was intensified by news reports demonstrating the appalling conditions in which people with EVD are treated and health care workers are expected to work. Controversies about drug development processes were exacerbated by news that ZMapp, an investigational agent available in very limited supply, was accessible to foreign nationals but inaccessible to Africans worst affected by the disease.2

While the research for EVD treatments and vaccines is urgent, research priorities cannot be allowed to divert resources from critical patient care and public health activities, as proven interventions should be funded ahead of research in order to resolve the crisis.3 This makes the process by which research is incorporated into the battle for survival of patients with EVD of the greatest practical and moral importance. The paucity of health care delivery systems in most parts of Africa renders decision making about EVD drug and vaccine trial designs hugely significant. First, there is the need to know whether experimental therapies increase survival. Second, there is the “rule of rescue,”4 which supports the use of any plausible and available treatment to reduce mortality and morbidity. This is applicable in the context of EVD management given the extreme suffering experienced by people infected with EVD. Finally, it is necessary to evaluate what therapies or vaccines work best among the experimental candidates. Together, these considerations mean that there are complex decisions to be made about the design and implementation of EVD clinical research.

We will argue in this chapter for the necessity to be open to a range of methodological approaches to EVD clinical research and to ensure community-consultation mechanisms are in place to help shape the design and implementation of EVD-related clinical research. We also argue for the need to ensure post-trial benefits for affected communities and the need to strengthen the health care systems through investments made during the EVD research process.

EVD and the Controversy over Randomized Controlled Trials

Broadly perceived to produce objective, unbiased evidence of the highest quality, randomized controlled trials (RCTs) are frequently described as the “gold standard” of research. This belief is particularly strong for double-blinded RCTs, where neither the participants nor the researcher knows whether the randomization is to an active drug or a placebo/standard of care. It has been argued that RCTs are the best way to maximize social values and the scientific validity of EVD clinical research,5 and that the benefits of randomization are so substantial every opportunity to use RCTs should be taken.6 For regulatory purposes, RCTs are required to provide the needed evidence to draw conclusions about drug safety and efficacy for licensing.7

The RCT methodology, however, has been criticized for requiring that the best interests of current patients be sacrificed, via random allocation to different study arms, for the best interests of future patients who will benefit from the knowledge produced by the study.8 Many therefore consider that RCTs are justified only in conditions of clinical equipoise: where the relevant scientific or medical community holds, on reasonable grounds, that the superiority of an experimental agent has not been established.9 Equipoise is broadly acknowledged as the moral justification for randomization in health care research, as the interests of participants are not “sacrificed” in the case where the difference between treatment modalities is unknown.10

Dawson11 argues that EVD clinical trials present a situation of genuine uncertainty, and therefore justify randomization to experimental treatment versus control. However, we argue that while there may be equipoise for EVD clinical trials, equipoise may not be a sufficient moral justification for randomization for EVD clinical trials in the absence of an effective standard of care for EVD;12 in the presence of high patient mortality;13 and when there are alternate experimental options that provide useful data.14

Unfortunately, much of the dialogue about clinical trial design for EVD drug and vaccine research has been driven by biomedical perspectives of appropriate clinical trial designs and how best to determine the efficacy and effectiveness of the experimental products. Little consideration has been given to the historical, political, and social context of the lives of those worst affected by EVD, which could impact the recruitment, retention, and use of EVD therapies and are factors that would affect the success of any clinical trial conducted, irrespective of design. This is significant, because EVD is a disease of poverty and neglected health systems.15 The current global emphasis has, unfortunately, not focused on addressing the drivers of EVD, thereby potentiating future outbreaks in a socioeconomic context that places affected nations at risk of not being able to purchase the developed EVD drugs or vaccines without donor support.

This chapter takes a look at the historical, cultural, and social context of the lives of the population worst affected by EVD and the implications for the design and implementation of EVD drug clinical trials. However, we recognize that for effective responses for EVD management and control in the affected region, a lot more needs to be done than investing in EVD drug and vaccine development: Many of these structural factors, which are of public health importance, would also affect access to and uptake of EVD treatment and vaccines when developed.

History, the State, and Implications for EVD Response

Sierra Leone and Liberia have both been affected by many years of civil war, and Guinea has suffered many years of coups and political violence. The civil disruption in these countries left political systems fragile with citizens who are sensitive to signals of marginalization. Journalists report antagonism toward the political system in these countries, resulting from the unresponsiveness of political elites to the needs of citizens and the failure to care enough for society.16 The relationship of citizens with government is plagued with distrust and feelings of abandonment and frustration. Against this backdrop, the EVD epidemic underscored the existing social and political tensions and undermined the cooperation required for effective public health responses. Health workers on strike from an Ebola treatment unit, who were promised but then denied increased pay for risking their lives, is but one example of this tension.17

There is also a history of distrust of foreign nationals promulgated by the government following the incursion of foreigners into domestic politics in the wake of humanitarian and refugee programs that followed the period of civil crisis.18 This distrust of “foreign elements” is exemplified by local attacks on a Médecins Sans Frontières treatment center in Guinea, and denial of access to foreign NGOs and government agents in some settlements during the epidemic.19 This distrust is a potential source of crisis during EVD research if the research is perceived as exploitative or perpetuating inequity.20

Civil disruptions have had negative impacts on health and health care costs well beyond the conflict period.21 Conflict typically disrupts economic activity, reduces access to clean water and food, and diverts resources from health care.22 It also results in breakdown of systems for public health surveillance, epidemic outbreak monitoring, and health communication networks,23 with associated increases in incidence of infectious disease24 and disease-related deaths.25 Conflict also results in the loss of health professionals to death, injury, or emigration; disruption of governance structures and supply lines; and interruption of health campaigns, in addition to increased demands for care.26 This is exemplified by the low ranking of Sierra Leone, Liberia, and Guinea on the human development index.27 These weakened health care systems became nonresponsive during the Ebola epidemic. The gaps were so egregious that the system itself became a vector for the spread of the disease.28

Post-wartime, countries in the Ebola zone experienced recurrent outbreaks of infectious diseases such as cholera, yellow fever, Lassa fever, dengue fever, typhoid,29 measles, and meningitis.30 The control of these infectious disease outbreaks has always depended on response and support from the international community. However, at the time of the EVD outbreak, “donor fatigue” had set in, and the international community was engaged in setting up fledgling systems to reduce donor dependency.31 The fragile transitional systems were unable to handle the EVD outbreak, because it was outside routine health care management.32 The lateness of the response from the international community, combined with the decentralization of a health care system that could have helped facilitate an EVD surveillance response, further contributed to poor epidemic control. Indigenous responses also required that changes be made to routine state activities, with implications for political, social and economic changes.33 These changes take time and resulted in further delays in state response to the epidemic.

Local values—including culture and social norms—are an essential factor in making a decision about the selection of drugs that move though clinical testing.34 There is, however, very little debate about how local values can influence EVD drug trial design. Waldman and Nieburg35 rightly acknowledge that with EVD crisis management, Western scientific thinking has been forced to confront the realities of other cultures. Where attitudes toward prevention of illness and their treatment collide, as is expected in situations with EVD management, proposals that make significant efforts to incorporate scientific and local values have the best chance for success.

As an example of how culture and international scientific research are necessarily intertwined, Zvonareva et al.36 provide empirical data to show how South African participants in international research viewed their participation as a contribution toward the collective benefit of the community. To the participants, research was a form of partnership between communities and researchers with the aim of achieving better health. Sociocultural practices and understandings validate or invalidate the practice of science and how community members make sense of the clinical trial process.37 Local community perspectives of research are also informed by indigenous accounts of what is right and wrong.38 A history of colonial exploitation, foreigners driving the EVD research process, and the prospect of benefits derivable from a clinical trial process have significant import for shaping connotations, perspectives, and reporting of the EVD epidemic in the local histories of these communities.

While there are biomedical perspectives about the science and ethics of clinical trial design, values rooted in culture and local moral traditions influence research participation.39 For this reason, it is an ethical imperative to have visible, meaningful local input in the design of the response to the EVD epidemic to ensure the research is understood as ethical and humanely focused and does not violate harmonious relationships within the society. When there are differences in ethical perspective between cultures, parties must engage and negotiate to resolve these differences.40 The importance of collaborative research that remains cognizant of social values and respects legitimate ethical expectations of research participants can therefore not be overemphasized.

Design and Implementation of EVD Clinical Trials in EVD-Affected Countries

For the most part, EVD drug and vaccine clinical trials would be classified as international research conducted in resource-limited settings. Concerns therefore arise about beneficiaries of the outcome of research: Researchers advance their careers, pharmaceutical companies make gains, and citizens in the resource-poor Ebola zone would have to contend with the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights to access EVD drugs and vaccines when developed. How then can people affected by EVD benefit from EVD research in the short, medium, and long term?

There are four possible ways that this could be achieved, namely: (1) ensure study protocols are developed in consultation with local researchers; (2) prioritize community engagement throughout the research design and implementation process; (3) establish concrete plans regarding future access to EVD drugs during future outbreaks; and (4) foster investment in health care infrastructure. We consider these processes to be mechanisms through which EVD research can be sensitive to the histories, cultures, and social norms of the respective communities, thereby promoting co-ownership of the EVD research process.

Study Protocols

EVD study protocols should be developed in collaboration with researchers who work in countries where studies are to be conducted. Local researchers should be intellectually invested in the planning and implementation of the research from its conceptualizing through to its implementation, data analysis, and data interpretation.

Engagement of local researchers in the design of EVD research allows for in-country discussions on study specimen ownership, study specimen shipment process, and data sharing prior to biobanking. This process also helps ensure that local social, political, and cultural perspectives inform the design of clinical trials. Acknowledging the legitimacy of cultural norms should promote exploration of alternative research designs that can produce desired outcomes with levels of scientific validity similar to what would be expected for more traditional clinical trial designs.

Possible alternative research designs proposed for testing Ebola interventions include a cluster-randomized trial, wherein different therapies are offered in parallel at different sites.41 This design requires (a) that a consistent standard of care is applied rigorously at each trial site, and (b) the experimental therapies have a significant enough impact that the “noise” in the statistical analysis is outweighed by a dramatic reduction in mortality. Unfortunately, the first condition is very challenging to achieve with the current EVD epidemic in West Africa, and the second condition is unlikely to be met.

A second possibility is the sequential randomized control trial (SRCT) design,42 wherein randomization occurs at the group (health service) level, with active experimental treatments available to all participants. The trial has built-in adaptation features, so that if or when a treatment shows superior results, more participants could be switched to that intervention. Data would be collected using an observational protocol. Again, this design requires consistent and agreed-upon standards of nonexperimental care between sites, with failure to achieve this being a confounder.

A third possibility is the use of a multistage approach (MSA) including both nonrandomized and randomized elements. When the outcomes of the MSA approach were compared to SRCT and conventional RCT, both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful.43 One major threat to the validity of the results of the non-randomized components of the MSA, as mentioned, is the inability to ensure the consistency of the standard of care provided to patients at the treatment sites.

A further alternative EVD vaccine trial design is the “stepped-wedge” trial design, in which randomization occurs at the group or community level, and each group eventually receives the intervention in a staggered, step-wise timeline.44 Similar adaptive non-randomized clinical trial designs are being implemented for ongoing EVD vaccines clinical trials.

An example of stepped-wedge trial design is the alternative “ring” design used in Guinea to determine the efficacy of a recombinant, replication-competent vesicular stomatitis virus-based vaccine in the phase III Ebola ça Suffit trial.45 The study actively recruited every person who had come into contact with an Ebola-infected person for vaccination with the experimental product: Some were offered vaccination immediately, while others received the vaccination after 21 days delay. The interim results showed that the study product was 100% protective in the group that was immediately vaccinated. While true vaccine efficacy is likely to be lower than that figure, as vaccines that produce sterilizing immunity are extremely rare, the study result suggest the tested candidate vaccine is likely to be effective at the population level. The outcome of the Ebola ça Suffit trial justifies the use of alternative clinical trial designs to establish the efficacy of a candidate product during a critical emergency health crisis.

Community Engagement

The community engagement process should promote public dialogue to address misconceptions; foster equity and justice in participant selection, recruitment, and retention strategies; and encourage honest discussions about risks, benefits, and future drug and vaccine access.46 It should also help community advocates become knowledgeable about scientific aspects of proposed trials in order to contribute meaningfully to discussions about clinical trial design.47 Public dialogue facilitates the design of culturally sensitive and politically appropriate clinical-trial implementation processes. Such public dialogue should engage researchers and community representatives affected by current and past EVD epidemics, since their experiences help enrich the research design process. Community partnership with researchers would have significant impact on the future narrative of the EVD response in local community histories.48 Dialogue helps shape perception of clinical research.49

Future Drug Access

Concrete plans need to be made to ensure access to EVD drugs during future EVD outbreaks. This would help to avoid exploitation of countries and citizens that have invested human resources in the EVD drugs trials. The Declaration of Helsinki and the Council for International Organizations of Medical Sciences ethical guidelines stipulate that research protocols submitted to ethics committee for review must discuss post-trial access to experimental products. The determination of the efficacy or effectiveness of EVD drugs and vaccines cannot be the end of EVD researchers’ investment in the EVD response. EVD clinical trials need to be planned with the view of ensuring future access to developed drugs for regions that participated in the research. We recognize that planning for post-trial access to an as-yet unlicensed product is difficult: There may be no plan for manufacture or scale-up. This highlights the need for public-private partnerships to ensure production in the event that a product is shown safe and effective. In this, pharmaceutical firms ought to be credited with proactively engaging in the development of EVD vaccines50 and drug development in collaboration with government agencies and academic institutions.

Health Care Infrastructure

While we do appreciate that it is the state’s responsibility to address health care provision for its citizens, we feel that research enterprises that conduct clinical trials in countries affected by EVD epidemics have a moral duty to invest in building health care systems and structures. Such efforts would contribute to long-term human and infrastructural development for future research in neglected tropical diseases. The current EVD epidemic shows the global community that these neglected diseases have the potential to escalate to become global health security threats51 when health systems fail. Investing in developing effective health systems in the region prior to the next crisis should be a priority of the global collective.52 This would enhance EVD treatment and vaccine research that needs to take place during the next EVD outbreak.53 The global commitment to health security and health research should inevitably lead to the commitment of research projects to strengthen the health systems within which EVD clinical trials are conducted.

There are propositions that the limited available resources for EVD management and control should be invested in strengthening the health care system rather than EVD research.54 While we do not believe in an “either/or” approach for EVD management and control, we do strongly agree on the need to mobilize local resources and empower local people to provide the required care needed to increase the chances of survival of EVD patients vis à vis prompt diagnosis; intensive supportive treatment within a health care facility; and critical public health interventions, such as contact tracing, isolation, surveillance, safe burial, and effective community engagement.

Conclusion

The design and implementation of research that establishes the efficacy and effectiveness of EVD drugs and vaccines is important. RCTs are widely recognized to address these questions, but may not always be appropriate for use in a crisis situation when there is an urgent need to treat large numbers of people55 and to establish ways for people to better protect themselves from infection. It is possible to generate evidence about the effectiveness of EVD drug therapy and vaccines without the ethical and moral challenges associated with standard RCT design.

The options for drug and vaccine clinical trials should not only be informed by science, but also by the history, politics, culture, and social norms of the communities to be engaged in clinical trials. Trial design for EVD research should promote equity in experimental drug access during an epidemic with high case fatality, especially in the face of a history of inequitable access to experimental interventions (e.g., ZMapp), past colonial exploitation, distrust of foreigners, differing local understandings of ethics, and the collegial expectations of sharing outcomes of research.

EVD drug and vaccine researchers should explore the suitability of alternative approaches to RCTs for conducting clinical trials in EVD-affected zones. Study designs must also include best supportive care, even if it is not locally available. The known standard of care for EVD management should not be denied patients enrolled in clinical trials, regardless of the local context of where the study is conducted. Finally, our argument for alternative clinical trial designs does not the preclude the implementation of conventional RCTs for the investigation of EVD drugs and vaccines during an EVD epidemic where supportive therapy is optimal, health systems are efficient, research literacy is high, community understanding and perception of biomedical ethics align perfectly with researchers’ perspectives, and there is no history of exploitation and distrust of foreigners.

Acknowledgments

The dialogues on the ethics of Ebola management we held with our colleagues, with whom we worked between 2014 and 2015, shaped our thoughts for this manuscript: Aminu Yakubu, Brandon Brown, Jamee Tegli, and Kristin Peterson. We also thank Liza Dawson and Patricia Kingori for finding time to critically review the manuscript and providing useful comments.