Ethics of Conducting Clinical Research in an Outbreak Setting

"The approaches to clinical research in outbreak settings developed for Ebola virus have moved the field forward...and will improve the responses to SARS-CoV-2 and future epidemics. However, many challenges remain including poverty, lack of surveillance systems, inadequate health care delivery systems, and fear and misinformation in the countries impacted."

Many international thought leaders, including members of the World Health Organization (WHO) Ethics Working Group, affirmed an ethical obligation to conduct research during West Africa's 2014 Ebola epidemic. The ethical challenges that arose during the resulting clinical studies, the ways these challenges were addressed, and the lessons learned for dealing with future outbreaks were the subject of a National Academy of Medicine (NAM) committee report titled Integrating Clinical Research into Epidemic Response: The Ebola Experience. This review summarises that report, discusses how the ethical dialogue changed in the later Ebola outbreak in the Democratic Republic of the Congo (DRC) and worldwide COVID-19 outbreak, and what the implications are for efforts to include pregnant women and children in present and future therapeutic and vaccine trials.

Based on earlier conclusions reached about the ethics of conducting research in the context of the human immunodeficiency virus (HIV), the NAM committee report identified 7 core scientific and ethical requirements:

1. Scientific and social value - The knowledge gained must justify the risks to the subjects and the costs associated with the trials.
2. Respect for persons - There is an obligation to provide understandable, relevant, and reliable information to potential study participants about the need for the research, the choices available to them, the risks and benefits of each option, and what will happen if they choose or decline to participate in the research.
3. Community engagement - It is critical to engage communities early in the dialogue about the study design to enable informed decision-making; communication channels must be open and messages clear.
4. Concern for participant welfare and interests - In addition to concerns about study risks, other potential risks include harm due to confidentiality breaches and the stigma associated with participation.
5. A favourable risk-benefit balance - Research should be conducted only when there is true uncertainty that one of the interventions is superior to the others.
6. Justice in the distribution of benefits and burdens - Research should not focus on the health needs of some groups while neglecting the needs of others.
7. Post-trial access - Participants should be able to acquire the tested agents that proved effective.

The review next provides a summary of both therapeutic and vaccine research conducted in the 2014 Ebola outbreak. Selecting the control arm for the trials proved to be one of the most controversial issues. One of the problems that complicated this and other aspects of the trials was the abundance of rumours at the onset of the outbreak about the source of Ebola virus and the role of developed countries in causing the outbreak. As a result, there was initial distrust of local and national governments and international scientists who came to assist with the outbreak. Initial planning was mostly top-down with little community input or respect for community traditions or religion, particularly around burying the dead. With time, communications improved, local communities became more involved, and international researchers engaged community leaders.

The NAM committee acknowledged that future epidemics of Ebola or other emerging pathogens would occur and that planning for these outbreaks was needed and should involve:

• Strengthening capacity - The NAM report identified 6 specific areas for improvement, including inexperienced in-country ethics review boards that lacked resources, experience, training, and information management systems.
• Engaging communities - The NAM report strongly supported early input of social scientists to facilitate community engagement, stressing that community leaders should participate from the onset in response planning, public health management, and research conduct. They urged that, during the interepidemic periods, it would be helpful if meaningful interactions between the community and the public health sector could be established.
• Facilitating international coordination and collaboration - The NAM report highlighted that the discovery process for new therapeutic agents and vaccines and the infrastructure for trial conduct should be accomplished through an international collaborative effort consisting of stakeholders from governments, foundations, pharmaceutical companies, academia, humanitarian organisations, and the WHO.

As outlined here, several expert advisory panels were formed to take up these recommendations in preparing for subsequent outbreaks. One of the groups formed (in 2017) was the Coalition for Epidemic Preparedness Innovations (CEPI), which is a partnership between public, private, philanthropic, and civil society organisations to develop vaccines for future epidemics and ensure equitable access to vaccines. Part of its work involves supporting and coordinating activities to improve the collective responses to epidemics, strengthen capacity in at-risk countries, and advance the regulatory science for vaccine development.

The review looks at how things changed during the Ebola epidemic that was declared on August 1 2018 in the North Kivu and Ituri provinces of the DRC. The authors explain that, since the 2014 Ebola outbreak, there have been substantial improvements in medical management (e.g., an effective vaccine). However, there is widespread community mistrust, and violent attacks on health workers and Ebola responders have occurred. There is also resentment over security forces surrounding the response. Despite these challenges, the new understanding as articulated in the NEM report and subsequent developments meant that "ethical and scientifically sound research could be conducted during an Ebola outbreak in the DRC."

The authors note that, historically, pregnant women and children have been excluded from most clinical trials due to perception of them as vulnerable. However, over the last several decades, the momentum has shifted, with the understanding that, "Provided with the potential risks and benefits of the experimental product and available evidence for safety, pregnant women are capable of judging their participation in a clinical trial, just as they decide about their routine care." To further progress in the immunisation of pregnant women, a multiyear Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) project funded by the Wellcome Trust was established to develop consensus-driven, actionable ethics guidance on equitably including the interests of pregnant women and their offspring in vaccine research and development (R&D) during epidemics. Despite these and other efforts to include pregnant women in clinical trials, their inclusion has been slow to be implemented.

Next, the review examines issues related to the inclusion of children, noting that international regulatory guidance documents include criteria to protect children participating in clinical research and ethically including them by limiting harm, differentiating risk, and considering the complex characteristics of children.

Shifting toward the context of the current (as of this writing) outbreak of COVID-19, the review looks at vaccine and therapeutic developments that may bring the ethical issues faced earlier during Ebola and other epidemics into light.

In summary, this review argues that progress has been made in terms of ethics understanding and expertise in the conduct of studies during outbreaks. One can only hope that this increased wisdom, and the planning that has taken place in the interim, can shape our response to the COVID-19 pandemic and the therapeutic and vaccine trials that are being undertaken.