Participant Recruitment, Consent and Post-trial Access to Interventions

Abstract

Humanitarian emergencies, including public health crises such as epidemics, can overwhelm local resources and severely disrupt the functioning of communities and societies. Conducting research during or in the immediate aftermath of an emergency poses increased practical and ethical challenges, not least because the need to rapidly generate valuable knowledge must be constantly balanced with the principles of humanitarian assistance. This chapter provides an overview of key ethical considerations relevant to recruitment, consent and post-trial access to interventions in pandemic contexts, and proposes an “ethics in practice” approach. Research conducted during emergencies is unavoidably context – and time – sensitive, making generalized guidance difficult. The aim of this chapter is thus not to prescribe a checklist for decision-making, but to assist researchers and practitioners to reflect on and discern what constitutes ethical practice during exceptional times. In particular, public health emergencies highlight tensions that can arise between balancing the rights and interests of research participants with the health needs of the population. Careful consideration is also needed of the necessity of minimising risks and maximising benefits, including ensuring that recruitment processes are sensitive to potentially altered risk perceptions and impacts of increased vulnerability on power imbalances. The importance of establishing and maintaining trust is reviewed, particularly when asymmetries in knowledge and access to resources are heightened in complex and challenging pandemic contexts. The five case studies presented in this chapter invite readers to reflect on ethical challenges that research during public health emergencies presents, particularly in connection with processes for communicating with and recruiting participants which have been adapted in pandemic contexts; potential risks to research participants and study staff; and with the rights participants in control groups may have to access experimental products.

9.1 Introduction

Humanitarian emergencies, including public health crises such as epidemics, are large-scale natural or human-induced phenomena that overwhelm local resources and severely disrupt the functioning of a community or society. Conducting research during or in the immediate aftermath of an emergency poses increased practical and ethical challenges, not least because the need to rapidly generate valuable knowledge must be constantly balanced with the principles of humanitarian assistance. The five case studies presented in this chapter invite readers to reflect on some of the ethical challenges that research during public health emergencies presents, particularly in connection with participant recruitment and consent and with the post-trial obligations of researchers to participants.

In this introduction to this set of case studies, we highlight three key ethical considerations relevant to recruitment, consent and post-trial access to interventions. While our reflections are grounded in established principles that govern research ethics and are endorsed in key international guidelines, their application will depend on the unique set of circumstances in which activities take place. We thus suggest an “ethics in practice” approach. Research conducted during emergencies is unavoidably context- and time-sensitive, making generalized guidance difficult. Our aim here is not to prescribe a checklist for decision-making but to assist researchers and practitioners to reflect on and discern what constitutes ethical practice during exceptional times.

9.2 Balancing the Rights and Interests of Research Participants with the Health Needs of the Population

Public health emergencies, such as the COVID-19 pandemic, acutely highlight some of the tensions that can arise when trying to balance the interests of individuals (e.g. research participants and/or patients) with those of the population as a whole. To this end, it may be helpful to consider the key ethical principles and values that underpin medical and research ethics, in order to weigh up ethical considerations when there is a conflict between the interests of an individual and the wider population.

In the context of medical practice, clinical or medical ethics are primarily concerned with navigating the conflicts arising when determining what’s best for the specific patient (Wilkinson et al. 2008). Research ethics, on the other hand, addresses conflicts that arise when balancing the interests of research participants/patients in general against those of medical science (CIOMS 2016). In research, as well as in clinical practice, respect for the participant’s or patient’s autonomy is a central ethical concern, highlighted by the emphasis on individual informed consent (to undergo treatment or to participate in research). In the context of a pandemic, in which the whole population is significantly impacted by an infectious disease outbreak, and collective action is fundamental to controlling it, individual-level concerns must be weighed against concerns for the population as a whole (population health ethics). This notwithstanding, it is essential that the need to reduce suffering for the population as a whole is carefully balanced against the rights and interests of individuals (Nuffield Council on Bioethics 2020).

One area where this need for balance is particularly evident is in the consent process. Seeking informed and voluntary consent is a fundamental way of ensuring that the rights and best interests of the individual are respected. However, where conditions on the ground are such that standard consent procedures become unfeasible, other appropriate approaches may need to be developed. In these cases, the principle of minimizing risks to health (such as the risks arising from face-to-face consent procedures) needs to be balanced against the principle of respect for individuals, which requires participation in research to be voluntary, informed and competent (CIOMS 2016; Nuffield Council on Bioethics 2020). Such conditions may be more difficult to determine when the interaction between researchers and participants is physically distanced and takes place remotely. Balancing these two principles may require that in addition to developing adaptive and innovative consent procedures that are ethically sound and work in an emergency context (e.g. remote consent via telephone), researchers need to pay particular attention to the relational aspect of the consent process (Nuffield Council on Bioethics 2020; WHO 2020).

The need to adapt consent processes in emergency contexts can, in fact, give rise to ethically problematic situations, for example with regard to assessing the validity and voluntariness of consent taken over the phone, especially when this involves minors, as discussed in Case 9.1. While these are practical difficulties for which there are no perfect solutions, allowing time to establish rapport with participants and creating a safe space of mutual recognition and respect will play an important role. Furthermore, the extent to which consent should be viewed as an on-going and dynamic process, rather than a discrete event, requires consideration. Case 9.2 offers an illustrative example of the need for such dynamic consent, especially when rapidly changing situations can lead to varying attitudes, behaviours and practices.

During public health emergencies such as the COVID-19 pandemic, unusual circumstances may arise where obtaining individual-level consent is not practical or even possible at all (Goldman and Gelinas 2021; Goyal et al. 2021; Largent et al. 2021). Case 9.3 prompts us to reflect on whether research ethics committees should make exceptions to standard requirements for individual informed consent in the context of COVID-19, and if so what the limits to this should be. Similarly, Case 9.4 asks us to consider how – in the context of a pandemic – consent processes for post-mortem research should be adapted and whether family consent can be ethically waived, given the heightened infection risks associated with consent protocols involving face-to-face and group consultations. In these and other cases, such as research conducted in emergency situations with patients who are comatose or incompetent, waiving consent may be justifiable if the research can demonstrate high social and scientific value and the waiver of consent is accompanied by community-level consultations to ensure acceptability (CIOMS 2016; Largent et al. 2021). In deciding to adapt or waive consent procedures, it is important to consider not only risk factors (see also below), cultural considerations and logistics, but also whether a waiver can be justified by the potential benefits that the research may generate.

Balancing population health needs against the needs and rights of participants requires going beyond consent, and including considerations about post-research obligations and the fair sharing of benefits (CIOMS 2016). This may require reassessing what is owed to participants/patients after the completion of a research study or trial (e.g. sharing research results, data and/or knowledge and interventions generated by the research, building local health infrastructure and capacity) (Lairumbi et al. 2011, 2012). For example, Case 9.5 prompts us to reflect on whether participants assigned to the placebo arm of a clinical trial should be prioritized to receive the treatment over other priority groups, once its efficacy and safety have been established.

While established ethical principles require researchers to provide fair benefits to participants, these considerations need to be weighed against the broader public health needs at the time, and against considerations about fair allocation of resources, including health workers’ time. Case 9.2 reminds us that in the midst of a health emergency, frontline staff can very quickly become overstretched, and therefore it is more important than ever to weigh up the social value of research against pressing public health needs. These value assessments will certainly have different weightings than if made in “normal” times and may result in a greater prioritization of frontline activity, especially when research may be important and of benefit to individuals and communities in the long term but does not directly contribute to the immediate emergency response.

Balancing the need to provide benefits to participants against broader public health needs may also entail adopting a broad view of research benefits, which includes not only short-term and direct benefits (e.g. priority access to drugs or effective treatments) but also long-term and indirect benefits. Research (including research conducted during health crises) may be justified in terms of the benefits that individual participants derive from improvements to overall population health (e.g. reduced transmission of infection as a result of effective treatments/vaccines). During outbreaks, heightened infection risk in the population represents a threat to every person, and so benefits at the population level (including reducing transmission and developing effective treatments and vaccines) are also likely to translate into benefits at the individual level (including a reduced risk of infection and a higher chance of survival). However even when no direct benefits of research participation are envisaged, researchers still have a duty of care towards participants and should minimize risks and address any adverse effects resulting from the research, as we outline below. It is also important that questions about post-research access to interventions and obligations to research participants are carefully considered prior to the enrolment of participants so that these can be clearly communicated from the outset. This will help ensure that participants can weigh up the benefits and burdens of the proposed study and come to an informed decision about whether to take part.

9.3 Minimizing Risks and Maximizing Benefits

Infectious disease outbreaks are challenging circumstances in which to conduct health research. While most of the ethical issues that emerge when carrying out research during epidemics are similar to those encountered in “normal” times, one key difference involves the assessment of risk during an epidemic or pandemic. During outbreaks, risks inherent in the research process may be faced by researchers and frontline staff, as well as participants. There is a duty of care to consider the well-being of participants alongside the welfare of frontline staff, including researchers. Therefore, actions must be taken to identify and mitigate foreseeable risks generated by epidemics and pandemics (see Cases 9.2 and 9.4) (Nuffield Council on Bioethics 2020).

Under normal circumstances, health research entails both risks and benefits to participants, and for this reason, any potential physical, psychological or social harms must be identified prior to recruiting participants and justified in terms of the scientific and social value of the research (CIOMS 2016; Nuffield Council on Bioethics 2020). The value of research is understood as generating knowledge to reduce suffering and improve people’s health. During emergencies, it may be particularly important to ensure evaluations of risks, benefits and the social and scientific value of research are informed by consultation with relevant populations. Measures to minimize and manage potential risks should be established, and a threshold of risk should be agreed upon, prior to ethical review. Participants must understand the risks of participating in the research and the measures being taken to manage such risks. However, during emerging infectious disease outbreaks, risks may be difficult to predict and evaluate, and researchers, participants and ethics committees have to make decisions in the context of uncertainty (Hofmann 2020).

During infectious disease outbreaks, existing vulnerabilities are often exacerbated and new ones can emerge, as discussed in Chap. 8. Under conditions of high vulnerability and uncertainty, participants may be inclined to make risk–benefit assessments that lead them to accept levels of risk they would not accept under normal circumstances (Macioce 2021). Recruitment processes must therefore be sensitive to risk perceptions and power imbalances that may result from increased vulnerability, as well as the social dynamics of the communities participating in the research (CIOMS 2016; Nuffield Council on Bioethics 2020). However, care should be taken that protection of vulnerable individuals or groups does not translate into recruitment criteria that unfairly disadvantage these groups, excluding them from the benefits of participating in research. Risk–benefit evaluations during research design, review and conduct need to include not only the risks associated with research participation but also any risks of non-participation, especially when a dearth of research may result, for example, in inadequate care for the groups excluded (Nuffield Council on Bioethics 2020).

9.4 Establishing and Maintaining Trust

Trust plays an important role in the conduct of scientific research. Yet trust is a complex concept, with no agreed definition, and therefore differences – even subtle ones – in understandings can lead to contradictory or inconsistent action, which can undermine the research enterprise (Resnik 2011). Trust is above all a relationship – between people, between people and groups, or between groups. It facilitates social cooperation (Whitbeck 1995), but it is not without cost: trust requires taking risks and embracing uncertainty (because there’s no guarantee that the person or institution deemed trustworthy will act as expected). Trust can create moral and/or legal duties for the person/institution being trusted, whether implicitly or explicitly, to “keep their promise”.

Because scientific research is a relational activity involving many collaborative interactions – between scientists, between scientists and research participants, between scientists and granting agencies, publishers, universities, etc. – trust is key (Resnik 2011; Kerasidou 2017). If parties do not fulfil the expectations placed upon them, the cooperation upon which much of the research enterprise depends becomes difficult, if not impossible. For this reason, trust goes hand in hand with respect. In the context of the researcher–participant relationship, trust is presupposed in the latter’s consent to take part in the research (O’Neill 2002). Such presupposed trust in research places obligations on researchers to respect participants, including to avoid harming them, to protect their data, ensure confidentiality, act in the interests of society and not be unduly influenced by financial or other personal interests (Kass et al. 1996; Miller and Weijer 2006). Breaches of these obligations undermine trust and can lead to participants withdrawing from the research, or worse, declining to participate altogether. Case 9.4 demonstrates the importance of diligence and socio-cultural sensitivity when communicating with prospective participants and communities in order to establish and maintain trust. However, trust and corresponding obligations exist within highly asymmetrical relationships, owing to the power differential between researchers and participants (Karnieli-Miller et al. 2009), which renders the latter vulnerable and dependent on the former. This is especially so when the lines between research and intervention become blurred (Case 9.3), as is often the case in emergency contexts.

Crisis contexts such as pandemics and other public health emergencies can exacerbate asymmetries in knowledge and access to resources, and therefore power differentials, thus affecting perceptions of trustworthiness (Fox et al. 2020). For example, as mentioned above, heightened health needs may create false expectations about the benefits of research and could lead to misunderstandings, especially when research participation is perceived as the only way for individuals to satisfy basic needs (Kingori 2015). Such “empty choice” situations could be avoided, for example by collaborating with humanitarian or governmental organizations to provide services. Establishing, where possible, viable and visible referral mechanisms to such organizations, irrespective of research participation, may discourage enrolment in research studies as a measure of last resort to access basic services. Researchers also need to prevent misplaced trust and manage unrealistic expectations by being clear and transparent with participants and communities during the consent process about their research goals, including any limitations on post-trial access to experimental treatments, as illustrated by Case 9.5.

Trusting relationships between researchers, participants and local communities can be strengthened in emergency situations. Case 9.2 illustrates that trust in those tasked with representing the interests of the communities can sometimes offer legitimacy to a research study which is well beyond that conferred by the contractual model of informed consent (Appiah 2021). The relationship between trust, authority and consent deserves more attention than we can give it here. Suffice to say that, if research is a relational activity, as suggested above, the process of consent must also be relational, with trust as its implied currency. Researchers and the institutions they represent must trade in this currency with both individuals and communities. While emergency conditions may present additional challenges, appropriate engagement provides a forum for debate and negotiation that builds trust and safeguards the values and interests of the community as a whole at a time when this is most needed.

Nevertheless, trusting relationships can also be undermined by fear and misinformation. Uncertainty during crises alters normal patterns of information-seeking behaviour and this creates conditions rife for the spread of fake news and conspiracy theories, especially via social media (Huang and Carley 2020). The extent to which this can impact on the participant–researcher relationship is captured in Case 9.4, where challenges related to cultural acceptability are compounded by fears fuelled by misinformation. In complex environments like this, researchers have a greater responsibility to build trusting relationships with participants through effective engagement that enables participants to understand the acceptability of the proposed research, to respond to concerns and to ensure transparency and accountability. Equally critical is developing strong communication processes during recruitment and throughout the research to give participants clear information about the nature of the research and the potential benefits and risks, as well as addressing any conflicts of interest. Case 9.2 shows how people’s attitudes to risk in rapidly evolving situations may be constantly changing as information (and misinformation) flows help consolidate new – albeit not always appropriate – risk management strategies, underscoring the importance of engagement and effective communication. Trustworthiness, together with timely, honest and effective communication, plays a key role in countering the diffusion of misinformation and promoting participation in research.

Conducting research in settings affected by public health emergencies or other humanitarian crises is challenging on many fronts, not least when it comes to accessing and recruiting participants. When face-to-face interactions pose significant personal and public health risks, online technologies can be used to seek consent (Case 9.4) or conduct interviews (Case 9.1). However, while online tools may offer the flexibility to circumvent participants’ constraints and avoid health risks to researchers (Case 9.2), they also present ethical and methodological challenges (Brown 2018; Chiumento et al. 2018; Lo Iacono et al. 2016). The physical separation between researcher and participant can affect the research interaction itself, whether this is because of technical issues (connectivity, digital literacy) or simply due to the difficulties inherent in establishing a rapport and trust at a distance. Privacy and confidentiality may be more difficult to guarantee, especially if participants do not have access to private spaces or need to use shared devices (Case 9.1). Physical distance also increases the risk of misreading visual clues that may signal unease or lack of understanding. Finally, the disembodiment of the interaction may make it easier for participants to adopt a different persona or even fake their identity. All this can undermine trust and the authenticity of the relationship. When adapting research to online platforms, careful consideration is needed of researchers’ responsibilities to get to know their participants, including allowing sufficient time for the interaction and being sensitive to unusual patterns of behaviour, especially when open exchange is not possible for whatever reason.

9.5 Conclusion

In sum, humanitarian emergencies such as infectious disease outbreaks require more, not less, ethical consideration, when difficult trade-offs between the common good and the good of the individual must be made; when an environment of heightened risk alters the balance between harms and benefits; and when trust can be strengthened by the shared struggle but also jeopardized by distorted perceptions and misinformation. Faced with decisions of life and death, researchers may feel that the moral imperative is to generate knowledge to minimize suffering, promote health and save lives, but this must not come at the cost of violating the paramount principle of respect for participants and communities. For those conducting research under these difficult circumstances, this entails a greater responsibility to develop ethically adaptive, responsive, innovative and proportionate approaches to research. Finding effective and efficient solutions under time pressure must be undertaken without neglecting compliance with internationally agreed ethical principles and guidelines. We recognize that achieving this requires ethical judgement to determine how such principles and guidelines should be applied in unique research contexts. We hope the cases in this chapter encourage ethical reflection and help researchers and reviewers who are confronted with the challenges of developing, reviewing and conducting research during public health emergencies.

Appendices

Case 9.1: Ethical Challenges Arising When Recruiting Adolescent Minors by Telephone

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

Keywords

Consent; Vulnerability and inclusion; Privacy and confidentiality; Safety and participant protection; Researcher roles and responsibilities; Research design and adaption; Qualitative research; Non COVID-19 research; Digital and remote healthcare and research

This case describes the ethical challenges arising when informed consent for participation in research is sought by telephone from a minor. “John”, aged 12, was living with his mother and members of his extended family. He shared a mobile phone with his mother and siblings. Researchers at a research institute in Africa were conducting research on the impact of HIV interventions among young people 12–17 years old. The researchers advertised the study on the community radio station, and used local networks to recruit the young people. When the country went into lockdown in response to COVID-19, the decision was made that all recruitment at the research institute had to be virtual. The researchers called John’s mother to explain the study objectives and procedures, then asked if they could talk to John. John’s mother expressed interest and was keen for John to participate in the study. The researchers cautioned John’s mother that he had the right to refuse to participate even if she consented to him taking part. John’s mother handed the phone to him as the family members shared the phone. John assented to take part in research.

John was reticent when discussing the research over the phone, and the researcher frequently offered him opportunities to ask questions or say if he was unclear about any part of the study. The researcher would often ask John to paraphrase the information provided about the study and in response he expressed the desire to proceed with the consent process without referring to the information. The researcher did not want to make John uncomfortable and so did not press him to repeat the study information. However, there were concerns about John’s comprehension and whether he felt under pressure to hurry through the informed consent process. The researcher also wanted to ensure that John understood the consent process without keeping him on the phone for “too long”. Consequently, the researcher was anxious about whether the consent was informed and voluntary, and whether to discontinue the informed process despite John’s expressed desire to continue.

When John was asked if he could find a quiet private place to minimize disruptions and ensure his privacy during the call, he consulted his mother, and they decided together that he should remain in the same room as her. Given John’s age and the socio-cultural context, the mother’s concerns and protectiveness were understandable and respected. Still, the researcher wondered if John’s privacy was compromised, and whether his reticence might have been caused by the lack of privacy.

Questions

• 1. Given the stigma associated with HIV in the community, the participant’s lack of private telephone and private room, is it ethically acceptable to ask for consent to this type of research via phone? Why?

• 2. Given the researcher’s concerns during the consent process, should John be enrolled in this study? Why?

• 3. How should the rights of adolescents be protected when consent processes must be conducted by phone?

• 4. What responsibilities do researchers have to ensure that consent to research sought over the phone is meaningful and voluntary?

Case 9.2: Quantitative and Qualitative Research into Attitudes Towards COVID-19

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

Keywords

Consent; Research design and adaption; Safety and participant protection; Risk/benefit analysis; Community engagement and participatory processes; Research priority setting; Qualitative research; Researcher safety; Digital and remote healthcare and research

At the onset of the COVID-19 pandemic, a team of social scientists set out to undertake a quantitative survey to determine knowledge, understanding and attitudes towards COVID-19 among residents of two large rural communities in an Asian country. Community leaders were approached and appraised of the research study, and their support for the study was obtained. It was expected that the results from the survey would help in the development of informational and educational strategies and guide public policy. A questionnaire was developed and applied using a cluster sampling technique. In total, 30 clusters (wherein all houses within a cluster would be surveyed) in each of the two rural communities were selected and the survey commenced. During the data collection process the researchers were assisted by community health workers who had received online training in administering the survey. The health workers were preoccupied with other responsibilities and, when seeking to administer the questionnaire, found that many prospective participants were reluctant to participate and needed encouragement to do so. Obtaining written consent was not always easy as respondents – who were largely non-literate – were disinclined to have the information sheet read out to them and to give their signature/thumb impression. They believed that as their community leaders were cognizant of this study and had given support, it was all right for them to participate.

Towards the end of the third month of data collection, the research team noticed a distinct reduction in people’s sense of fear towards COVID-19. This was in sharp contrast to their experiences at the beginning of the process, when people feared even stepping out of their homes and were adhering to preventive measures such as face masks and social distancing. The health workers reported that in addition to a sense of complacency, people were resorting to the use of various traditional practices like consuming turmeric water and other herbal remedies that they felt would protect them from COVID-19.

To better understand this change in behaviour and corroborate the quantitative survey findings, the researchers sought to conduct a small qualitative study with a sample of residents from the two rural communities. One of the strengths of qualitative research is its capacity to explore and obtain deep insights into a phenomenon of interest. A revised proposal, with the proposed inclusion of a qualitative sub-study, was submitted to the research ethics committee for approval.

The qualitative study proposed to collect data via in-depth face-to-face interviews with participants. Each interview would take about an hour to complete as it would be an open-ended, exploratory process allowing respondents to express their thoughts, opinions and feelings. In addition, the interviews would need to be conducted privately and audio-recorded in a quiet place with minimal external noise. Invariably this would be inside the homes of the respondents, which are usually small and not always well ventilated. The risk of exposure to COVID-19 for both interviewer and interviewee was therefore higher than for the survey and it therefore did not receive ethics approval. One suggestion was to adapt the research methods and conduct the interviews via an online platform.

Questions

• 1. During the quantitative survey, researchers were required to seek individual written consent from participants. Should the requirement for such consent be revised in a pandemic context? Why?

• 2. When reviewing the proposed qualitative study, what considerations should the ethics committee take into account when determining whether the research risks are justifiable, managed and minimized to acceptable levels?

• 3. In this rural setting, some participants may be unable to participate in an online interview because of lack of access to the equipment needed, poor internet connectivity, and limited experience with online platforms. Given the need to minimize infection risks, what responsibilities arise to ensure that they do not get left out of research?

• 4. In this pandemic context, where the health workers assisting researchers already have multiple competing responsibilities, how should the proposed qualitative study be prioritized among other research priorities and public health priorities? Who should make such decisions and what ethical considerations should they take into account?

Case 9.3: Seeking Consent to Research Involving the Use of Convalescent Plasma from COVID-19 Donors in the Treatment of Cancer Patients

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

Keywords

Consent; Risk/benefit analysis; Researcher roles and responsibilities; Digital and remote healthcare and research

Cancer patients are at greater risk of developing COVID-19 than the general population, and those who contract it are at much greater risk of serious complications and death, probably as a result of the immunosuppression associated with their cancer treatment. In addition, cancer patients have a higher risk of developing blood clots, which can play a fundamental role in the pathogenesis of severe COVID-19 (Mei and Hu 2020).

The use of convalescent plasma from patients who have recovered from known viral infections has shown successful results in the treatment of SARS-CoV-1, MERS, influenza AH1N1 and Ebola, among others (Mupapa et al. 1999; Mair-Jenkins et al. 2015). In Latin America, a study was therefore proposed to explore the value of convalescent plasma in the population and specifically in adult cancer patients (aged 18+) who met criteria for severe COVID-19 with two or more poor prognostic factors for cancer. Patients would be grouped according to whether they had severe COVID-19 or COVID-19 with poor prognostic factors. These groups would then be subdivided into patients with and without cancer.

Following the administration of convalescent plasma to SARS-CoV-1 patients, varying results were reported, possibly attributable to the timing of the infusion (before or after 14 days from symptom onset) and lack of standardization of antibody titres. This study proposal involved the administration of two units of 200 ml of convalescent plasma to all patients who met the inclusion criteria and consented to take part, and analysis of the safety and impact of convalescent plasma on morbidity and mortality. The study would also evaluate the presence of other factors that affected patient outcomes in terms of mortality, including the length of time participants stayed in an intensive care unit, and in hospital.

The aim of the study was to evaluate whether the administration of convalescent plasma could decrease COVID-19 morbidity and mortality in patients with severe cancer. The most serious risks associated with the research were relatively rare and included the following:

• 1. Transfusion Related Acute Lung Injury (TRALI). Although a known risk in the context of COVID-19, TRALI is very difficult to identify since, in most cases when suspecting this complication, the patient is already in acute respiratory failure with damaged lungs.

• 2. Allergic reactions and anaphylaxis, which were estimated to be between 1 and 3 percent. Most of these reactions would be of a mild and transitory nature and would not require the transfusion to be suspended.

• 3. Transfusion-related volume overload. This is an infrequent condition, which the researchers proposed to manage and prevent by administering only 200 ml of convalescent plasma, at a slow rate of infusion, per session.

Patients would be invited to give consent and required to sign an informed consent form before participating in this study. If prospective participants were not competent to give consent, signed written consent would be required from a legal representative or a family member. This would create significant challenges, as it was current standard practice to isolate people with COVID-19 and to require all their contacts to quarantine for 14 days. It would therefore be difficult for research staff to meet with family members in person.

Questions

• 1. In a pandemic, should a research ethics committee make exceptions to standard requirements for informed consent? If so, what might be the limits to these exceptions?

• 2. Where it may not be possible to meet prospective participants’ family members or legal representatives to obtain signed written consent, are there other ethically acceptable ways of seeking and documenting consent for this type of research?

• 3. In settings where many families do not have access to digital technologies, is it appropriate to request that participants’ family members or legal representatives provide signed consent via email? Why?

• 4. What responsibilities should researchers have to evaluate and respond to potential socio-economic barriers to research participation?

References

• Mair-Jenkins, J., M. Saavedra-Campos, J.K. Baillie, P. Cleary, F.M. Khaw, W.S. Lim, S. Makki, K.D. Rooney, J.S. Nguyen-Van-Tam, and C.R. Beck (Convalescent Plasma Study Group). 2015. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. Journal of Infectious Diseases 211(1): 80–90. https://doi.org/10.1093/infdis/jiu396.

• Mei, H., and Y. Hu. 2020. Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19. Zhonghua Xue Ye Xue Za Zhi 41(3): 185–191. Chinese. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0002.

• Mupapa, K., M. Massamba, K. Kibadi, K. Kuvula, A. Bwaka, M. Kipasa, R. Colebunders, and J.J. Muyembe-Tamfum. 1999. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. Journal of Infectious Diseases 179(Supplement_1): S18–S23.

Case 9.4: A Study Involving Minimally Invasive Tissue Sampling in Adults Who Died from COVID-19

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

Keywords

Consent; Researcher roles and responsibilities; Research design and adaption; Safety and participant protection; Researcher safety

The spread and severity of COVID-19 are influenced by complex factors that vary globally, demonstrating the importance of region-specific research to enhance prevention, management and treatment of the disease. However, the infectious nature of COVID-19, and the morbidity and mortality associated with it, as well as infection-control measures such as quarantine and restrictions on public gatherings, present ethical challenges for research practices, including consent processes and risk minimization strategies for the study team, the research participants and the community.

A study involving post-mortem minimally invasive tissue sampling to investigate the pathogenic processes of COVID-19 infections in the lungs among adults was being conducted at a tertiary hospital in Africa in order to identify therapeutic targets. The study was being conducted among adults who had died of COVID-19, non-COVID-19 lower respiratory infections and infectious non-pulmonary illnesses. Studies involving minimally invasive tissue sampling already present cultural acceptability challenges in this setting, owing to fears of organ harvesting and disfigurement of the body. These challenges were compounded by other problems, including misinformation about COVID-19, the social stigma and discrimination faced by affected families, public apprehension over measures aimed at preventing COVID-19, and physical assault of COVID-19 health-care workers in some communities.

9.1.1 Communicating About the Study to Families

Considering the misinformation about COVID-19 present in the community, one of the study team’s aims was to ensure the bereaved family or next of kin had enough information to make informed decisions. The study team could not inform patients or their next of kin about the study while they were in hospital because the patients were sick and family presence on the ward was strictly limited. The study team were also concerned that rumours circulating after previous studies could lead the next of kin to think that health-care workers had been negligent in the care of their family member in order to enrol them into the study after they died. The study team reflected on the safest, most culturally sensitive and ethically sound way of informing the next of kin about the study after the death of their family member. The idea of engaging a health-care worker who was both a study team member and a front-line worker in the hospital ward to notify the family about the study was considered to introduce a potential conflict of interest. As such, health-care workers who were not part of the study team were asked to notify the study team about a death and to seek consent from the next of kin to pass on their contact details.

After an initial phone call with the next of kin, the study team felt that a face-to-face meeting was important to enable a sensitive and sufficiently detailed discussion about the study, share the consent form and obtain informed consent. Traditionally in the study setting, decisions regarding the deceased involve many family members, as well as friends and sometimes community figures. The study team felt that visiting the house of the deceased for these discussions posed significant risks. The team also considered that assembling large groups of people at the hospital presented its own logistical challenges and carried infection risks. In the absence of clear ethical guidelines on how consent should be sought for post-mortem research in the context of the pandemic, the study team carefully weighed up cultural, logistical and safety factors that could determine which family members should give consent. These factors included patrilineal and matrilineal family systems; the age, gender and marital status of the deceased; and the availability of close family members, given that the study was conducted in an urban setting where most people had migrated for employment or business purposes. The legitimate next of kin to give consent was therefore determined by each family with guidance from the research team.

9.1.2 Risks to Family, Research Staff and the Community

Apart from the risks of physical harm to study team members if they visited the next of kin at their home, the study team also considered the public health risks of asking the next of kin to use public transport to travel to the hospital for the consent process. In addition, where the next of kin had been in close contact with the deceased, according to regulations they needed to be in quarantine. The study team developed a decision-making tree to cross-check all these details before inviting the next of kin to the facility. They also provided a study vehicle and personal protective equipment to minimize the risk of infection.

Questions

• 1. How should communication with patients and the next of kin about post-mortem research be adapted in the context of the pandemic?

• 2. How should consent processes for post-mortem research be adapted in the context of the pandemic? Can family consent be ethically waived in the context of the pandemic, given the greater good that could emerge from research on COVID-19 in the absence of proven treatment? Why?

• 3. What types of risks might study staff and next of kin face during discussions about this research in the context of the pandemic? How should these be minimized?

Case 9.5: COVID-19 Clinical Trials: Placebo Group Participants and the Right to Access the Experimental Product

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

Keywords

Access to experimental treatments; Resource allocation; Regulatory review; Vulnerability and inclusion; Risk/benefit analysis; Post trial follow up and monitoring; Placebo control; Vaccines

After the declaration of the COVID-19 pandemic in early 2020, scientific research accelerated with the objective of preventing and effectively treating COVID-19. The efforts of the global scientific community led to the development of more than 300 COVID-19 vaccine projects. In 2021 studies demonstrated that new vaccines may play an essential role in protecting individuals and reducing the spread of the virus (Forni and Mantovani 2021).

In a South American country, two double-blind multi-centre Phase III clinical trials with an experimental group and a control group got underway in 2020. In the studies a COVID-19 vaccine was given to the experimental group and a placebo to the control group. One of the clinical trials was coordinated by a public institution studying an inactivated SARS-CoV-2 vaccine, which aimed to stimulate the immune system to produce antibodies with a reduced risk of adverse events. The other clinical trial was coordinated by a pharmaceutical company and evaluated a live attenuated vaccine which incorporated a chimpanzee adenovirus.

The participants in these clinical trials were adult volunteers, with no history of infection with SARS-CoV-2, who provided care for patients with COVID-19. Exclusion criteria included pregnancy or plans to become pregnant within the next 3 months, specific illnesses, and health-care conditions requiring medications that would alter immune responses. In both Phase III trials the effectiveness of the experimental vaccines was demonstrated, which enabled emergency use authorization and approval by local regulatory agencies.

Following this approval, the government established a national COVID-19 immunization plan and requested that all doses produced by the two institutions be made available to the government for the immunization of the priority group in the initial phase of the campaign – front-line health professionals. This directly impacted the capacity of the two institutions to offer the vaccines to the volunteers in the placebo group of each trial. The volunteers in the clinical trials began receiving information about whether they had been in the experimental or control group 2 weeks after the national immunization plan started.

Questions

• 1. What are the ethical implications of the government’s request for all of the vaccine doses produced by the two research institutions?

• 2. Since the research provided evidence on the efficacy and safety of two vaccines during the pandemic, should participants in the studies’ control groups be prioritized to receive the vaccine over other priority groups? Why?

• 3. Once the vaccines have been shown to be efficacious and safe, should participants be informed about whether they were allocated to the control or experimental arm of the study? Why?

• 4. Are the inclusion and exclusion criteria for these studies appropriate and justifiable in the context of the COVID-19 pandemic? Why?

Reference

• Forni, G., and A. Mantovani. 2021. COVID-19 vaccines: Where we stand and challenges ahead. Cell Death & Differentiation 28(2): 626–639. https://doi.org/10.1038/s41418-020-00720-9.