Introduction: Research Ethics and Health Policy in Epidemics and Pandemics

Abstract

Global health emergencies such as the COVID-19 pandemic are contexts in which it is critical to draw upon learning from prior research and to conduct novel research to inform real-time decision-making and pandemic responses. While research is vitally important, however, emergencies are radically non-ideal contexts for its conduct, due to exceptional uncertainty, urgency, disruption, health needs, and strain on existing health systems, amongst other challenges. This generates novel ethical challenges and a broader conception of research ethics is necessary to effectively address the complexity of pandemic research contexts. Going beyond traditional approaches to research ethics centring on the design of specific studies, this broader conception requires consideration of fundamental questions relating to the exercise of power and influence throughout research pathways, and a broader attention to both salient ethical issues, and the ethical responsibilities of stakeholders. These include important questions about responsibilities to gather evidence and generate knowledge systematically during emergencies, to implement policy responses in ways that are amenable to evaluation, and even potential moral obligations to participate in research. In situations of heightened uncertainty, additional questions arise about what constitutes sufficient evidence to justify the development and implementation of policy responses, and the responsibilities of scientific and social science researchers involved in policy-making processes. The four cases in this chapter prompt reflection on evolving and at times competing values and responsibilities of policy-makers, regulators, health authorities and researchers during the design and conduct of research, and proposed early implementation of research findings. These cases highlight issues arising when conducting research of national importance in a pandemic, where researchers are required to liaise with authorities responsible for pandemic responses and address complex ethical issues, including protecting the interests of participants and publics when tensions arise between prioritising the completion of research and accelerating the rollout of novel health interventions. This chapter invites reflection on the practical ethical implications of commitments to undertake research during emergencies, including the nature and scope of the relevant responsibilities of a range of stakeholders.

Global health emergencies such as the COVID-19 pandemic are inevitably both unique and familiar events: some aspects of them can be anticipated and others are unexpected. Outbreaks, epidemics and pandemics have long been part of the human experience and pandemic preparedness is vital. But in any particular emergency the preparations already in place and the assumptions underpinning them will always need to be modified in the light of the emergence of novel pathogen strains and their impacts, changes in human behaviour, and a range of other relevant factors. This suggests an inevitable tension between, on the one hand, the importance of ensuring that health policy and practice in the context of an emergency are informed by evidence gained from previous outbreaks – and by on-going infectious disease science – and, on the other hand, the inevitability that many aspects of a health emergency will be context-specific and unique. Given that knowledge in distinct, complex and evolving emergency situations can only ever be partial and incomplete, research addressing knowledge gaps has a vitally important contribution to make to effective responses to epidemics and pandemics. This highlights the importance both of learning from research conducted during previous pandemics and also of undertaking good-quality research in the current emergency to inform real-time decision-making.

Conducting research in outbreaks, epidemics and pandemics, however, presents an array of complex ethical challenges that need to be identified, analysed and addressed if it is to be successful and capable of commanding well-founded public trust and confidence. Some of these ethical issues will be familiar, but many will be new and/or will arise in combinations not previously encountered. Some of the most important of these ethical considerations arise out of the fact that research needs to be undertaken in circumstances in which societies, health systems, and capacities to conduct research and provide effective oversight of it, are under profound strain.

1.1 Taking a Broader Approach to “Research Ethics”

In this casebook our aim is to encourage an inclusive approach to research ethics which is adequate to address the complexity of conducting research in outbreaks, epidemics and pandemics. In doing so, we build to some extent upon the model set out in the Nuffield Council on Bioethics report on the ethics of research in global health emergencies in 2020, which argued that we need to take a much broader approach to research ethics than has traditionally been the case – both in terms of issues considered to be “ethical”, and of the individuals and organizations recognized as having ethical responsibilities (“duty bearers” such as funders, employers and governments). “In brief, ethics is not just about the behaviour of people on the ground, but also the functioning of processes that, however remote they may seem at times to front-line research workers and participants, exert powerful influence on the options actually open to those directly involved in research activities” (Nuffield Council on Bioethics 2020: 4).

Issues that are routinely included within independent ethical review processes, including the need for sensitive study design, well-designed information materials for prospective participants, and meaningful consent processes, are all at the heart of ethically conducted research. Flexible and responsive independent review processes that are sensitive to the time pressures inherent in the emergency are also essential. However, they are not enough. When thinking seriously about the ethical implications of research in emergencies, we need most of all to be alert to fundamental questions relating to the exercise of power and influence, asking ourselves questions such as: “Whose voices (and interests) are steering the choice of priority research topics?”; “Whose voices are determining the way that research is conducted?”; and “Who is going to benefit from this research?”. Questions of power and influence arise throughout the trajectory of research, from the scope of an initial funding call to the publication and feedback of findings. Such considerations prompt consideration of diverse aspects of research practice, including:

• The extent to which research is responsive to the multifaceted, differing and inequitable impact of emergencies.

• The ways in which those directly affected by emergencies are engaged in the research process, and the capacity of researchers to respond meaningfully to community input.

• The fairness of research collaborations and capacities of all collaborators to influence research priorities, design and conduct, and responsibilities to promote the welfare of front-line research workers.

• Responsibilities arising when seeking to share and access clinical, surveillance, pathogen and research data to support effective pandemic responses.

These considerations also engender ethical responsibilities for a very broad range of duty-bearers; research funders, research institutions, academic publishers, international and intergovernmental organizations, and national governments have policies and practices that profoundly affect how research is conducted.

1.2 Thematic Approach

The cases and chapter themes in this casebook illustrate and provide opportunities for reflection on the importance of a broad, contextually sensitive understanding of research ethics in emergencies. Each chapter includes case studies detailing lived experiences during 2020 and early 2021 to facilitate consideration of the complex ethical issues arising in practice during the COVID-19 pandemic, and their implication for future research in emergencies. The chapter themes are structured to reflect themes arising in the submitted case studies, and do not follow a structure common in research ethics standards, where topics such as research justification, risks and benefits, and consent are addressed sequentially. Chapter 2 addresses the moral complexity of research prioritization in emergencies, including decisions about deprioritising ongoing research. Chapter 3 outlines the importance of conducting rigorous research and appropriately disseminating research findings in non-ideal emergency contexts. Chapter 4 explores the ethical significance of distinguishing between research and non-research activities, such as surveillance, and the challenges that can arise when doing so in rapidly evolving pandemic contexts. Chapter 5 complements this discussion by exploring responsibilities to ensure that research is flexible and responsive to changing policy and evidentiary landscapes. Chapter 6 outlines the issues that can arise when seeking to adapt research review and oversight processes while maintaining substantive participant protections. Chapter 7 explores issues arising when seeking to share and maximise the utility of surveillance, clinical, pathogen and research data to inform pandemic responses. Chapter 8 focuses on responsibilities to ensure that research is appropriately responsive to populations and the inequitable impact of emergencies. Chapter 9 addresses the responsibilities of researchers to ensure that the interests of research participants and communities are appropriately respected when developing and conducting research during public health emergencies.

This first, introductory chapter focuses on the changing, and at times competing, obligations, values and priorities underpinning complex interactions between researchers, regulators and policy-makers during the design, conduct and modification of pandemic research, and early implementation of research findings, against a background of rapidly evolving public health policies and pandemic responses. The four case studies in this chapter illustrate and provide opportunities for reflection on the need for a broad, contextually sensitive understanding of research ethics. When research is prioritized in the pandemic, researchers may need to liaise not just with the typical stakeholders involved in the funding, design, review, conduct and oversight of research, but also to liaise directly with the national authorities who have responsibility for pandemic responses. The cases in this chapter highlight the complex considerations that can arise when research addresses knowledge gaps of national importance during a public health emergency, including adaptions to health-care delivery (Case 1.1), vaccine development (Case 1.2), SARS-CoV-2 infection and pathogenesis (Case 1.3) and COVID-19 epidemiology (Case 1.4). In such cases, direct engagement between researchers and authorities may be necessary for addressing complex ethical considerations, including tensions between prioritizing the conduct and completion of research to address knowledge gaps, accelerating the rollout of novel public health and clinical interventions and approaches, and protecting and promoting the interests of participants and the public.

1.3 The Ethical Importance of Research for Real-Time Policy and for the Benefit of Future Generations

In his book, ‘For the common good’ Alex London has recently argued that research is not a morally optional activity in a global health emergency (London 2022). Policy-makers, academics, research funders and health systems bear important responsibilities to gather evidence and generate knowledge systematically during emergencies to inform real-time policy-making. They also – importantly – have obligations to future generations. Just as we, to some extent at least, have benefited from research undertaken in previous emergencies, so too will those in the future have a right to expect us to have made systematic attempts at understanding the emergencies we have faced. This suggests that even in situations where it is unlikely that data gathering and analysis are going to inform policy-making during a current emergency, there are nonetheless important obligations to work to inform responses to future emergencies and provide an evidence base for future generations.

This also raises important ethical questions about whether members of the public, patients and so on have moral obligations to participate in such health research. Answers to this question are likely to vary depending on factors such as the risks of participation – how big is the risk and how serious the harm if the risk is realized? It might also depend on the nature of the risk. For example, is it a privacy risk, a risk to physical health, or a risk of some other kind? It seems reasonable to argue that in a situation where the risks were very low, those who are able to contribute to the generation of knowledge and understanding that have the potential to save lives and/or reduce suffering in future generations could have an obligation to do so. A good example might be participation in regular testing programmes or surveys aiming to understand changing levels of infection in the community. There will likely be limits to the risk it would be reasonable to expect anyone to take for others; but what are those limits? What is the nature and scope of the obligations to future generations in the context of an emergency? An important and related question is that of what level of risk in research is it ethically acceptable for researchers to offer to potential participants? Even if it is accepted that people have no obligation to participate in risky research it might perhaps be argued that it is nevertheless ethical to offer them the choice to take part under certain circumstances. Are there limits to the level of acceptable risk? Might this depend to some extent upon the level of background risk to which they are already subject in the context of a pandemic? (Bull et al. 2020).

Quite apart from the obligations of individuals to take part in research, those who develop and implement policy responses to pandemics have an obligation to do so in ways that are capable of generating generalizable knowledge to inform decisions in current and/or future emergencies. During the COVID-19 pandemic, many of the most important public health interventions have not been implemented in ways that have been amenable to either research or rigorous evaluation. Decisions to open or close schools, decisions to mandate face masks, decisions to allow public events have, for example, almost inevitably not been structured in ways capable of providing evidence about their impacts and efficacy. In such cases there are important obligations to act – to set policy – on the basis of such evidence as exists, and to structure policy in ways conducive to generating knowledge – as well as to undertake research as an integral part of public health policy-making in an emergency (Marteau et al. 2022). “Following the science” has been an oft-heard phrase during the COVID-19 pandemic. However, there is also a sense in which policy needs to lead the science by creating the conditions for it and deciding to prioritize research and rigorous evaluation (Massinga Loembé et al. 2020).

The COVID-19 pandemic has also reemphasized that global health emergencies are never only about health. They have wide-ranging impacts, many of which may be as serious as those that affect “health” narrowly defined. Examples might be the impacts we have witnessed on education, on the economy, on employment and on a range of other socially and culturally important activities. This suggests that vitally important research during pandemics should include not only biomedical research but also social science and public health research on, for example, the impact of mask-wearing in schools on social development in young children. This and other possible examples illustrate that research methodologies adequate to making sense of a pandemic will appropriately vary, ranging all the way from classical vaccine studies (Case 1.2), through challenge studies (Case 1.3), to qualitative studies exploring the drivers of vaccine hesitancy (Duong et al. 2022; Momplaisir et al. 2021). In the context of a pandemic, the undertaking of each of these forms of research, both together and in combination, will generate novel ethical questions and require them to be resolved. Ethical issues associated with research prioritisation in a pandemic are addressed in Chap. 2. Examples of ethical issues arising out of the relevance of findings for the subsequent conduct of studies are discussed in Chap. 3 in the context of publication ethics and, in relation to adapting and adaptive trials, in Chap. 5.

1.4 Emergencies as Radically Non-ideal Contexts for Research

Although research is a vital part of pandemic response, in the context of any global health emergency in fact, the reality is that health emergencies are usually radically non-ideal contexts for rigorous research capable of meeting internationally accepted ethical standards. Some of the reasons for this have their origins in the rapidly changing landscape of public health policy and practice in the context of political and other pressures to “do something” or to do with tensions between health and other priorities, such as the economy. Other reasons arise out of the nature of the health emergency itself. As the Nuffield Council on Bioethics states,

Research in global health emergencies unavoidably takes place in non-ideal circumstances, characterised by disruption, uncertainty, and great health need. This can be compounded by competing claims for legitimacy, time pressures, confusion, and distress. These factors present significant practical challenges to ethical decision-making as practitioners struggle to align their ethical obligations to challenging and often chaotic circumstances. (Nuffield Council on Bioethics 2020, p. 76)

These shifting sands and competing commitments, values and priorities create a context in which rigorous research conducted to high ethical standards may be more difficult to achieve, as discussed in Chaps. 3 and 6. However, it is also these complex, dynamic and interconnected features of an emergency that make it imperative to conduct research to generate the new knowledge required for intelligent public health policy and response. Therefore, research is both important and ethically complicated.

1.5 Relationships Between Research and Practice

The arguments above suggest not only that research in the context of global health emergencies is important but also that such research needs to be part of, i.e. properly integrated within, public health responses to the emergency. It will sometimes, even if not in all cases, need to be based on access to real-time data generated by health authorities and be expected to inform the making of health policy.

Traditionally, research ethics guidelines have taken the view that research and practice should be kept separate for a range of reasons. Perhaps a fundamental concern historically has been to ensure that participants’ interests are appropriately protected more broadly (since they are no longer receiving tailored care but instead taking part in an activity designed primarily to gain generalizable knowledge) – given egregious examples where interests have been overridden purportedly for the “greater good” (see Chap. 3). More specifically, many of the arguments for maintaining a clear distinction between research and practice arise out of concerns about the validity of consent if there is the potential for lack of clarity about the distinction between therapeutic and research intentions. People may, for example, mistake research for clinical care. In practice, clear distinctions between research and practice may be blurred for a range of different reasons in different settings (see Chap. 4). In the context of global health emergencies, the appropriateness and achievability of a clear distinction between some forms of public health research and evolving public health activities may be at its least convincing. As Case 1.4 in this chapter demonstrates, distinguishing between activities can be problematized in real time during emergencies, resulting in notable complexities where, for example, the same activity can be designated research in one context or at one time, and as “clinical practice” in others. At the same time, it is important to recognise that such distinctions can have a substantial impact on public confidence during public health emergencies. Chapter 4 includes an interesting example of this in its discussion of the concerns that can arise when there is a lack of clarity about whether a novel vaccine is being offered as a proven public health intervention or as an experimental intervention as part of a clinical trial (Case 4.4 in Chap. 4).

1.6 Modifying Health Policy in the Context of Uncertainty and Open-Endedness

One of the reasons why global health emergencies are likely to constitute radically non-ideal contexts for research is that there is an inevitable mismatch between the timescales of research and those of policy-making. This means that policy decisions of various kinds, e.g. the beginning or ending of lockdowns, emergency use authorization and rollout of vaccines (Case 1.2), or the mandating of mask-wearing on public transport, will often need to be made before definitive evidence is available (even if such a thing is possible). This raises important and urgent questions with a strong value component. What constitutes sufficient evidence? When is the evidence good enough? Tensions such as these between the requirements for acceptable research standards of proof/certainty and those of policy-making in the public interest also, inevitably, require difficult ethical decisions. This is because such decisions will inevitably have implications for morally significant aspects of the lives of those affected by the policy. Policy changes may have implications for equity, or for the liberty or privacy of those affected, or they may have impacts on the well-being of patients and members of the public. People may die or be harmed who would not otherwise have been affected in this way. The making of such policies is ethically difficult where there is good evidence, and even the very best evidence is rarely definitive. Under conditions of uncertainty, ethical complexity is further compounded by morally significant questions relating to the levels of certainty/uncertainty compatible with responsible decision-making. Of course, while there are some situations in which waiting longer might enable the science to progress to a point at which uncertainty was reduced, in many cases – perhaps most – the facts on the ground will change in ways that suggest greater certainty is unlikely in the time available. What does responsible, evidence-based health policy-making look like in such situations?

In other situations, such as in Case 1.1, questions arise not so much in relation to uncertainty but in the context of interventions which research shows to offer “less-than-ideal” solutions. In Case 1.1 the example given is of a technological approach to the remote monitoring of COVID-19 patients at home. What ethical questions are raised by the use of interventions that are considered to be imperfect, or based on uncertain or incomplete data, in the service of public health? Is something better than nothing? If so, when and under what conditions?

1.7 The Impact of Policy Choices on the Ethical Acceptability of Research

There are times when the direction of impact goes the other way, i.e. when changes in policy in response to emerging evidence can raise important questions about the ethics of on-going or proposed research. A good example of this is provided by Case 1.2, in which a placebo-controlled vaccine study is impacted by the authorization of the vaccine under study for public health use under emergency or conditional authorisation. Another example, Case 1.3, is one in which the scientific justification for research judged to be ethically acceptable early in the pandemic, urgent even, required re-evaluation, given the unexpected speed of the development and deployment of new vaccines during the COVID-19 pandemic.

1.8 The Responsibilities of Researchers Who Are Part of the Policy-Making Process

One of the most striking features of the current COVID-19 pandemic has been the high-profile involvement of scientific and social science researchers in the policy-making process. Many governments have claimed in their responses to the pandemics to have been “following the science” and senior scientists have played important and highly visible advisory roles in the making of public policy. In addition to these high-profile roles, many other researchers from a range of disciplines have conducted studies feeding into health policy locally, nationally and internationally. This has the potential to raise interesting and important questions relating to the ethics of scientific practice. Clearly such researchers have obligations to conduct their research to high standards of rigour and to meet the relevant ethical and professional requirements. However, the context of a global health emergency also has the potential to create situations in which difficult questions about the moral responsibilities of scientists arise. This might be because policy appears to contradict the best available evidence, or because evidence is being misinterpreted. It might also be because of a perceived responsibility to counteract the “post truth” aspects of much public, political and media debate. In the context of a public health emergency characterized by great suffering and conflicting beliefs, values and commitments, what are the moral responsibilities of infectious disease scientists, social scientists and other public health researchers?

1.9 Concluding Remarks

The broad approach to research ethics in epidemics and pandemics introduced in this chapter and used in this casebook, aims to capture a comprehensive and context-sensitive range of ethical questions arising in the complex contexts that are inevitably part of global health research on epidemics and pandemics. Our aim in the selection of chapter themes, and the use of cases exclusively drawn from lived experiences, has been to illustrate a range of ethical questions arising during the design and conduct of research, and publication and rollout of research outputs. Against this background, in this chapter we reflect on some of the changing, and at times competing, obligations, values and priorities underpinning complex interactions between researchers, regulators, policy-makers and health authorities when pandemic research is conducted in rapidly evolving research and policy landscapes. We invite reflection on the practical ethical implications of commitments to undertake research during emergencies, including the nature and scope of the relevant responsibilities of a range of stakeholders.

Appendices

Case 1.1: A Study on the Telemonitoring of COVID-19 Patients at Home

This case study was written by members of the case study author group.

Keywords

Boundaries between research, surveillance and rollout; Researcher roles and responsibilities; Resource allocation; Safety and participant protection; Data protection, access and sharing; Digital and remote healthcare and research

As the number of COVID-19 cases surged across the world, many hospitals reached their full capacity to admit and treat COVID-19 patients. In some countries, patients with no symptoms, or mild ones, were asked to quarantine and were assessed remotely by a health-care team, often through phone calls. However, this required a large number of health-care workers to contact patients daily to identify those whose conditions had deteriorated and who required admission to hospital (about 10%). A possible way of improving the monitoring process and reducing health-care workload is to develop automated symptom-monitoring systems. Such systems have been successfully deployed in other areas of medical practice.

1.1.1 Research

Professor E., a digital health expert, received an emergency call from clinical colleagues at a COVID-designated hospital, who asked if she could develop a way of monitoring their patients at home. The hospital had reached its full capacity and could not admit further patients. Those patients who were not admitted were being monitored at home; however, owing to a shortage of staff, they often did not receive calls from the hospital. Professor E. decided to convene a technical team, comprising the top students in her class, to find a solution to this problem. The idea was to develop a remote monitoring system using a chatbot (a computer system designed to simulate interactive conversation with users), which allowed patients to report their symptoms from home. Patients’ self-reported data would then be transmitted in real time to a medical dashboard, which could be accessed by the hospital health-care team. The system also had a decision support feature, which prompted patients to call the hospital hotline should they experience new symptoms, or if their condition deteriorated.

As this was a new health application, the team decided to conduct a research project to ensure that it was safe and effective before implementing it on a larger scale. The research team planned to host the system database on a public server to facilitate development, with the intention of transferring it to the hospital once it had been tested. However, the hospital had a data policy which required patient data to be stored on the hospital server. Nevertheless, in view of the nature of the research, both the ethics review committee and the hospital authorities approved the study after the research team assured them that the data would be stored securely and all the developers would sign a non-disclosure agreement. The technical and clinical teams worked tirelessly to develop the e-monitoring system, which was ready for pilot-testing within a week. The clinical team started to use the system with their patients, who were also monitored concurrently by the Hospital Public Health Surveillance Team as part of routine surveillance. While the system reduced the hospital workload significantly, the research team found that half of the patients who had reported that their health had deteriorated failed to call the hospital, and the clinical team still had to reach out to them. Furthermore, because of the overwhelming workload, there were a few near-misses, which were fortunately picked up by the dedicated Hospital Public Health Surveillance Team.

At the end of the study, the research team agreed that, although the system itself was effective and safe in monitoring patients’ conditions, implementing it in the real world would require a dedicated team of health-care workers to assess patients remotely to avoid delays in diagnosis and treatment. With the increasing number of patients, the sustainability of the close monitoring of the patients by the health-care team became questionable.

1.1.2 Surveillance

Following this, Professor E. received a call from the state Director of Health, who wanted to use the symptom-monitoring system her team had developed. The Director wanted Professor E.’s team to support the state in monitoring all the COVID-19 patients who were currently being monitored at home. Professor E. had several meetings with the technical and clinical teams at the state Health Office and realized that they did not have the technical expertise or clinical staff to implement the system safely. She also recognized that her technical and clinical teams were too small to cope with the substantial number of COVID-19 patients all over the state.

Professor E. decided to decline the state Director’s request but was under tremendous pressure to conform, as she received several calls a day from the state Health Office. She also felt guilty, as she wondered whether offering a less-than-ideal solution was better than no solution, as the patients were not being monitored properly at home anyway. On the other hand, she would feel responsible if the system was implemented without the necessary support, which might lead to a “false sense of security” among both patients and health-care workers, leading to delays in diagnosis and treatment, and possibly even deaths.

Questions

• 1. What ethical issues should an ethics committee consider when reviewing a digital health system during a pandemic, especially when its potential safety and efficacy are relatively unknown?

• 2. What types of safeguards for participants might need to be put into place for this type of research and why?

• 3. Should data security policies be more flexible for research in the context of a global health emergency? Why?

• 4. What ethical considerations should research teams and public health officials take into account when seeking to find a balance between “perfecting” the monitoring system and rolling it out to address urgent public health needs?

Case 1.2: Trial Unblinding Following Emergency Authorization of Vaccines

This case study was written by members of the case study author group.

Keywords

Boundaries between research, surveillance and rollout; Research design and adaption; Access to experimental treatments; Regulatory review; Researcher roles and responsibilities; Emergency Use Authorisation; Vaccines; Placebo control

Vaccines are a crucial tool for preventing and controlling epidemics and pandemics. Consequently, epidemics and pandemics can prompt a flurry of research to develop new vaccines for the pathogen in question. Usually, it takes many years to develop, authorize and deploy a vaccine. However, the COVID-19 pandemic has demonstrated that the vaccine research and development lifecycle – from the first in-human studies to manufacturing, authorization and deployment – can occur so rapidly that vaccines can be used in the same pandemic that prompted the vaccine research in the first place. In part, this may be facilitated through accelerated regulatory mechanisms that permit emergency use authorization (EUA) emergency/conditional authorization (ECA) (i.e. mechanisms that facilitate the public accessibility of investigational vaccines prior to the conclusion of their respective Phase III clinical trials or their licensure) – a process that deviates from the usual approach to vaccine licensing and market authorization (WHO ACT Accelerator Ethics and Governance Working Group 2020).

While laudable, the rapid development, authorization and deployment of novel vaccines in the COVID-19 pandemic raise complex ethical questions and present challenges for ongoing clinical trials for COVID-19 vaccines, due in part to the prospect of continued use of placebo controls in those trials (WHO ACT Accelerator Ethics and Governance Working Group 2020; Singh et al. 2021; Dal-Ré et al. 2021). Randomized, placebo-controlled trials play a key role in research pathways for evaluating the safety and efficacy of novel vaccines (Devereaux and Yusuf 2003). Yet, they raise ethical concerns when participants receiving placebos are deprived of an existing vaccine that is known to be effective against the pathogen in question (CIOMS 2016, see Guideline 5).

When an investigational vaccine receives EUA/ECA, this raises the question of whether participants in the placebo-control arms in ongoing trials for that vaccine are being deprived of an established effective intervention. If so, one might argue that such vaccine trials ought to be unblinded and that participants in placebo-control arms should be offered the vaccine from the trial’s experimental arm. On the other hand, one might argue that vaccines granted EUA/ECA do not yet meet the standard of an established effective intervention and that trials with placebo-control arms are still needed after EUA/ECA for purposes such as the following:

• further characterizing and understanding the duration of protection provided by the vaccine

• determining the efficacy of the vaccine in populations not previously included in clinical trials

• evaluating effectiveness for additional clinical endpoints not evaluated in previous clinical trials

• supporting the submission of applications for full market licensure.

This raises a unique challenge for vaccine research and regulation during pandemics, which has implications for national regulatory authorities, vaccine researchers, vaccine manufacturers and those responsible for the ethical review of research.

On 18 December 2020, the US Food and Drug Administration issued emergency use authorization for Moderna’s COVID-19 vaccine (US Food and Drug Administration 2020). Nevertheless, a randomized placebo-control trial was set to continue for up to 2 years, to evaluate the clinical efficacy and safety of the vaccine (ModernaTX, Inc. 2020). Americans not enrolled in the trial began to receive the vaccine, and a debate ensued about whether the trial should be unblinded, allowing participants to know whether they were receiving the vaccine or the placebo, so that they could choose to receive the vaccine if they hadn’t already done so (Lenzer 2020). Some argued that withholding an effective vaccine from trial participants would be unethical, pointing to the fact that one of the 185 participants who had received the placebo control had died of COVID-19 (Rubin 2021). Others argued that unblinding the trial would compromise its ability to yield reliable scientific data about the vaccine (Cohen 2020). Ultimately, Moderna chose to offer its vaccine to trial participants who had received a placebo (Peres 2021).

Questions

• 1. If a vaccine receives EUA/ECA for use during a pandemic, what are the competing ethical considerations that need to be addressed for ongoing vaccine research in this context? For example, is it ethical for clinical trials for other vaccines to continue using placebo-control arms? Why?

• 2. Should vaccines that have been granted EUA/ECA be viewed as an “effective established intervention”? Why?

• 3. Whose perspectives should matter when making decisions about the continued use of placebo-control arms for vaccine research in this context (e.g., national regulatory authorities, vaccine researchers, vaccine manufacturers, those responsible for the ethical review of research, research participants), and who ought to decide?

• 4. If the decision is made that it is not ethically required to unblind a trial of a vaccine with ECA, nor to provide the vaccine to the trial participants who received a placebo, is it ethically justifiable to seek to prohibit trial participants from accessing vaccines with ECA for the duration of the research? Why?

References

• CIOMS. 2016. International ethical guidelines for biomedical research involving human subjects, 4th edn. Geneva: Council for International Organizations of Medical Sciences.

• Cohen, J. 2020. Makers of successful COVID-19 vaccines wrestle with options for placebo recipients. Science. https://www.sciencemag.org/news/2020/12/makers-successful-covid-19-vaccine-wrestle-options-many-thousands-who-received-placebos.

• Dal-Ré, R., W. Orenstein, and A.L. Caplan. 2021. Being fair to participants in placebo-controlled COVID-19 vaccine trials. Nature Medicine 27: 938.

• Devereaux, P.J., and S. Yusuf. 2003. The evolution of the randomized controlled trial and its role in evidence-based decision making. Journal of Internal Medicine 254(2): 105–113.

• Lenzer, J. 2020. COVID-19: Should vaccine trials be unblinded? British Medical Journal 371: m4956.

• ModernaTX, Inc. 2020. Clinical study protocol: A Phase 3, randomized, stratified, observer-blind, placebo-controlled study to evaluate the efficacy, safety, and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine in adults aged 18 years and older. https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf.

• Peres J. 2021. Vaccine trial participants who received placebo now hop the line for the real thing for Pfizer, Moderna. Chicago Tribune, January 14. https://www.chicagotribune.com/coronavirus/ct-life-covid-vaccine-placebo-pfizer-moderna-janssen-trial-20210114-r6vzmohbs5ed5gstqwuxdhtria-story.html.

• Rubin, R. 2021. The price of success – How to evaluate COVID-19 vaccines when they’re available outside of clinical trials. Journal of the American Medical Association 325: 918–921.

• Singh, J.A., S. Kochhar, J. Wolff, and the WHO ACT-Accelerator Ethics and Governance Working Group. 2021. Placebo use and unblinding in COVID-19 vaccine trials: Recommendations of a WHO expert working group. Nature Medicine 27: 569–570. https://doi.org/10.1038/s41591-021-01299-5.

• US Food and Drug Administration. 2020. Moderna COVID-19 vaccine. https://www.federalregister.gov/documents/2021/01/19/2021-01022/authorizations-of-emergency-use-of-two-biological-products-during-the-covid-19-pandemic-availability.

• WHO Access to COVID-19 Tools (ACT) Accelerator Ethics and Governance Working Group. 2020. Emergency use designation of COVID-19 candidate vaccines: Ethical considerations for current and future COVID-19 placebo-controlled vaccine trials and trial unblinding. Policy Brief. Geneva: World Health Organization.

Case 1.3: COVID-19 Controlled Human Infection Studies

This case study was written by members of the case study author group.

Keywords

Social and scientific value; Risk/benefit analysis; Safety and participant protection; Ethical review; Community engagement and participatory processes; Controlled human infection studies

Within the context of the COVID-19 pandemic there has been international recognition of the urgent need to develop and distribute safe and effective vaccines globally (United Nations 2020). Vaccine development typically takes 10–20 years, including lengthy trials with human participants for the collection of sufficient evidence about safety and efficacy. In early 2020 calls were consequently made to consider conducting controlled human infection studies (CHIS) (also known as challenge studies) to inform and accelerate vaccine development (Plotkin and Caplan 2020; Eyal et al. 2020) and two COVID-19 CHIS commenced in 2021.

CHIS involve intentionally exposing participants to pathogens in order to study mechanisms of infection and disease and/or the efficacy of experimental vaccines or treatments. CHIS have made important contributions to the treatment and prevention of many infectious diseases (Jamrozik and Selgelid 2021). However, research methods which involve exposing healthy volunteers to a pathogen which can cause infection and disease may seem ethically counter-intuitive – particularly when natural infections with the pathogen can result in severe disease and death. Consequently, in the context of the COVID-19 pandemic, the ethical acceptability of exposing healthy volunteers to SARS-CoV-2 has been the subject of considerable interest and debate in the popular press, social media and academic literature (Callway 2020; Dawson et al. 2020; AVAC and TAG 2020). Two early consensus documents about the ethics of conducting COVID-19 CHIS neither sanctioned nor prohibited such research, but instead highlighted ethical issues requiring careful consideration during the design and review of any such studies (WHO Working Group for Guidance on Human Challenge Studies in COVID-19 2020; Jamrozik et al. 2021; Shah et al. 2020). These drew on broader norms of research ethics and focused on the need for substantial social and scientific value, appropriate risk–benefit profiles, careful site and participant selection, rigorous engagement and consent processes, appropriate compensation, and effective review, oversight and co-ordination.

In early 2020, a consortium of academics, industry collaborators, and the British government (through the Human Challenge Programme of the UK Vaccines Taskforce) began assessing the ethical and practical considerations associated with conducting COVID-19 CHIS. In April 2020, as plans to conduct COVID-19 CHIS progressed, a programme of public consultation and engagement commenced (HIC-Vac 2021). As an initial step, a series of online focus group discussions were held with 57 adults aged between 20 and 40 years. Attendees of the focus group discussions were given an outline of a COVID-19 CHIS protocol and asked about whether they thought the research should be done, what concerns study volunteers might have, how the risks of the research should be explained to potential volunteers, what they felt would constitute acceptable levels of financial compensation for participation, and whether they thought details of proposed studies should be made publicly available (Gbesemete et al. 2020) The results suggested the public was largely positive about the research, despite potential uncertainties about risk levels. During recruitment, the importance of being open and honest both about the risks of the research and about the levels of uncertainty regarding these, was highlighted. Respondents felt that the final decision about the acceptability of proposed COVID-19 CHIS should be made by the scientific community and ethical review committees (Gbesemete et al. 2020).

In December 2020, an application for ethical review of a COVID-19 CHIS, led by researchers from Imperial College, was submitted to the NHS Health Research Authority (Imperial College London 2020). The Authority convened a Specialist Ad Hoc Research Ethics Committee to review the protocol (NHS Health Research Authority 2021). In February 2021, ethical approval was granted to conduct the first COVID-19 CHIS in the world (Department for Business, Energy & Industrial Strategy and Kwarteng 2021). In April 2021 a study led by researchers from the University of Oxford received approval to conduct a second CHIS (University of Oxford 2021). The development and ethical review of both protocols were informed by the World Health Organization’s key criteria for the ethical acceptability of COVID-19 CHIS (WHO Working Group for Guidance on Human Challenge Studies in COVID-192020; Jamrozik et al. 2021) and the findings from public consultation and engagement activities. Key considerations arising during the ethical review included the justifications for conducting COVID-19 CHIS, and the appropriate management and minimization of research risks.

1.1.1 Research Justification

At the same time as the COVID-19 CHIS were being designed, vaccine development was progressing exceptionally rapidly. A small number of COVID-19 vaccines began receiving emergency and conditional use authorization before ethical review of the first COVID-19 CHIS took place. As the rollout of these first-generation vaccines began, questions arose about whether COVID-19 CHIS could still be justified. Researchers noted that COVID-19 CHIS still had an important role to play in addressing multiple critical research questions (Rapeport et al. 2021). These included identifying exactly what type of immune responses are needed for effective protection against COVID-19, which would enable accurate testing of whether people’s immune responses were likely to protect them from natural infection with COVID-19, and how durable such protection was likely to be. COVID-19 CHIS could also play an integral role in the development of next generation COVID-19 vaccines and of effective treatments, including monoclonal antibody therapies, as new strains of SARS-CoV-2 emerged. This could be especially important where it was necessary to test innovative methods that aimed to provide long-term protection irrespective of viral mutation by stimulating immune responses that were not easily measurable.

1.1.2 Research Risks

International consensus standards for research are clear that risks associated with research should not just be justified solely by the anticipated social and scientific value of research, but should also be reasonable, and appropriately managed and minimized. In the context of the pandemic, the evaluation of the risks of COVID-19 CHIS is complicated by the novelty of the pathogen, and the rapidly changing, and at times contested, evidentiary landscape (Bull et al. 2020). Risk management approaches in COVID-19 CHIS include restricting recruitment to young adult volunteers (aged 18–30) and conducting comprehensive testing and screening to exclude those with underlying conditions and ensure participants are healthy. The CHIS were also designed with cautious dose-escalation to optimize the infection rate if necessary, and started by exposing participants to very small amounts of SARS-CoV-2. Doses would only be incrementally increased if the initial lowest dose of SARS-CoV-2 was insufficient to infect half the participants, and the potential risks of increasing the dose could be appropriately managed and minimized. Any participants who developed COVID-19 symptoms were carefully assessed and received very early antiviral treatment, if required. The studies were conducted within residential quarantine units, where all participants were carefully monitored and discharged once it was confirmed they had not been infected, or if they were no longer infected or at risk of infecting others. Once discharged, participants were followed up for a year (Imperial College London 2020; University of Oxford 2021).

Questions

• 1. What key ethical issues should be addressed during the design and ethical review of CHIS proposed during an outbreak, epidemic or pandemic?

• 2. What ethical considerations should be taken into account during the design and conduct of consent processes for COVID-19 CHIS?

• 3. In studies which seek to address high-priority questions in a pandemic, are higher levels of risk and/or uncertainty about risks more ethically acceptable than in research which does not address such priorities? Why?

• 4. If controversial research is proposed during an epidemic or pandemic, is it ethically acceptable for it to be developed and reviewed without public consultation and engagement? Why?

References

• AVAC, and TAG (Treatment Action Group). 2020. AVAC and TAG statement on ethical conduct of SARS-CoV-2 vaccine challenge studies. AIDS Vaccine Advocacy Coalition. https://www.avac.org/blog/avac-and-tag-statement-ethical-conduct-sars-cov-2-vaccine-challenge-studies.

• Bull, S., E. Jamrozik, A. Binik, et al. 2020. SARS-CoV-2 challenge studies: Ethics and risk minimisation. Journal of Medical Ethics, September 25. https://doi.org/10.1136/medethics-2020-106504.

• Callway, E. 2020. Should scientists infect healthy people with the coronavirus to test vaccines? Radical proposal to conduct ‘human challenge’ studies could dramatically speed up vaccine research. Nature 580, March 26. https://doi.org/10.1038/d41586-020-00927-3.

• Dawson, L., J. Earl, and J. Livezey. 2020. SARS-CoV-2 human challenge trials: Too risky, too soon. Journal of Infectious Diseases 222(3): 514–516. https://doi.org/10.1093/infdis/jiaa314.

• Department for Business, Energy & Industrial Strategy, and K. Kwarteng. 2021. World’s first Coronavirus human challenge study receives ethics approval in the UK, February 17. https://www.gov.uk/government/news/worlds-first-coronavirus-human-challenge-study-receives-ethics-approval-in-the-uk.

• Eyal, N., M. Lipsitch, and P.G. Smith. 2020. Human challenge studies to accelerate Coronavirus vaccine licensure. Journal of Infectious Diseases 221(11): 1752–1756. https://doi.org/10.1093/infdis/jiaa152.

• Gbesemete, D., M. Barker, W.T. Lawrence, et al. 2020. Exploring the acceptability of controlled human infection with SARS-CoV2 – A public consultation. BMC Medicine 18. https://doi.org/10.1186/s12916-020-01670-2.

• HIC-Vac. 2021. How and when were the public involved in the study? https://www.hic-vac.org/public-information/human-infection-studies-coronavirus-covid-19/how-and-when-were-the-public.

• Imperial College London. 2020. COVID-19 Human Challenge Study. Leading the world’s first human challenge study for COVID-19. https://www.imperial.ac.uk/infectious-disease/research/human-challenge/.

• Jamrozik, E., and M. Selgelid. 2021. Human challenge studies in endemic settings ethical and regulatory issues. Springer briefs in ethics. Cham: Springer.

• Jamrozik, E., K. Littler, S. Bull, et al. 2021. Key criteria for the ethical acceptability of COVID-19 human challenge studies: Report of a WHO Working Group. Vaccine 39(4): 633–640. https://doi.org/10.1016/j.vaccine.2020.10.075.

• NHS Health Research Authority. 2021. Reviewing the world’s first COVID-19 challenge study, February 25. https://www.hra.nhs.uk/about-us/news-updates/reviewing-worlds-first-covid-19-challenge-study/.

• Plotkin, S.A., and A. Caplan. 2020. Extraordinary diseases require extraordinary solutions. Vaccine 38(24): 3987–3988. https://doi.org/10.1016/j.vaccine.2020.04.039.

• Rapeport, G., E. Smith, A. Gilbert, et al. 2021. SARS-CoV-2 human challenge studies – Establishing the model during an evolving pandemic. New England Journal of Medicine 385(11): 961–964.

• Shah, S.K., F.G. Miller, T.C. Darton, et al. 2020. Ethics of controlled human infection to study COVID-19. Science 368(6493): 832–834. https://doi.org/10.1126/science.abc1076.

• United Nations. 2020. “Landmark collaboration” to make COVID-19 testing and treatment available to all. UN News, April 24. https://news.un.org/en/story/2020/04/1062512.

• University of Oxford. 2021. Human challenge trial launches to study immune response to COVID-19, April 19. https://www.ox.ac.uk/news/2021-04-19-human-challenge-trial-launches-study-immune-response-covid-19.

• WHO Working Group for Guidance on Human Challenge Studies in COVID-19. 2020. Key criteria for the ethical acceptability of COVID-19 human challenge studies. Geneva: World Health Organization.

Case 1.4: Early-Stage Investigations into Infectious Diseases

This case study was written by members of the case study author group.

Keywords

Boundaries between research, surveillance and rollout; Data protection, access and sharing; Research design and adaption; Researcher roles and responsibilities; Consent; Sample access and sharing

Early investigations into the transmission of a new infection, such as COVID-19, usually rely initially on surveillance data, which are, ideally, routinely collected by public health authorities as part of standard practice. These data may be shared with researchers when there is an urgent need to develop new knowledge that will benefit the public health response and when the capacity for such sharing exists. Collection of any additional data not considered part of routine surveillance, including biological samples and data from specialized investigations such as genomic sequencing, may require additional protocols. Routine surveillance is likely to change over time to include more or different data as the new pathogen is better understood and tests are developed.

Study X was based on the WHO household transmission investigation protocol and aimed to use enhanced epidemiological surveillance and testing data to assess the transmissibility of SARS-CoV-2 as it began to circulate in the population of a high-income country (WHO 2020). The study identified early confirmed cases of COVID-19 and collected data and swab samples from their household contacts for up to 4 weeks, to provide detailed information about symptoms and transmission risk. Study X was national in its scope, gathering data in partnership with local public health agencies that each had a different way of operating. The experience of using a modified version of the WHO protocol in 2020 highlighted some ethical tensions of relevance to early investigation studies during this and future epidemics.

The implementation of Study X was complicated by the early categorization of study elements as either “public health” or “research”. Public health practice involved collecting routine surveillance data; what was “routine” was decided at the level of the local public health agency and differed from place to place. Anything additional was considered research. Following this distinction, data and sample collection were undertaken either as part of the emergency public health response, without explicit ethical approval, or as a research activity requiring standard ethical review and approval. At the beginning of Study X, ethics approval was sought to collect data that were not available through routine public health practice, and was granted. The ethics approval process was smooth; however, governance requirements caused delays.

During the COVID-19 response, public health agencies in the country were challenged by the demands of responding to a nascent infectious disease emergency and many were unable to devote resources to coordination with researchers. In some locations, researchers were able to enrol participants and gather data independently of local public health agencies, by leveraging existing research partnerships, but they continued to face challenges when attempting to access complementary, routinely collected data.

Early investigation studies are, by design, carried out as quickly as possible during times of great uncertainty and change. The types of data and samples collected by local health agencies changed during the period in which the study was conducted, owing to shifting information needs, the availability of new tests and increased capacity. Some of these changes meant that data and samples that were originally classified as “research” elements were now routinely collected. These shifts led to unanticipated consequences. Study X researchers were bound by approved study protocol for the collection of (for example) serological samples, because such samples were additional to routine collection. Later during the study, these samples were routinely collected by public health agencies. Study X researchers, however, were not able to obtain serological samples without explicit consent. This meant that samples that were added to routine public health practice after Study X began were not available to researchers.

Early investigations that took place in countries with on-going high-incidence COVID-19 infection generated results about transmission and severity quickly, and new knowledge about preventing infection was widely circulated locally and globally. Consequently, subsequent studies in lower-incidence contexts were taking place while public behaviour, government policy and case management were being altered in response to early findings. This created additional challenges for study eligibility and consistency, with, for example, early cases remaining in their households but later cases being removed to hotel quarantine.

Questions

• 1. How should research and public health practice be distinguished in studies that rely on routine public health surveillance but that may be enhanced by additional data and samples? What are the implications for ethics approval requirements, particularly given that early investigation studies are time-critical?

• 2. What responsibilities should public health and/or government agencies have to collaborate with researchers in an epidemic or pandemic?

• 3. What responsibilities do researchers have to communicate findings quickly and accessibly to public health agencies, including analysis of data derived independently of collaboration with such agencies?

• 4. In a pandemic, how should the design and conduct of context-specific studies be informed by results from other countries, if at all? Is there a point at which further context-specific research cannot be justified? Why?

Reference

WHO. 2020. Household transmission investigation protocol for coronavirus disease 2019 (COVID-19). Version 2.2, March 23. Geneva: World Health Organization. https://apps.who.int/iris/handle/10665/332040.