Boundaries Between Research, Surveillance and Monitored Emergency Use

Abstract

Responses to outbreaks, epidemics and pandemics involves a heterogeneous set of activities that aim to address threats to public health. In addition to research, non-research activities, such as prevention and control interventions, and surveillance, are conducted. The boundaries between research and non-research responses can rapidly blur during a public health emergency such as the COVID-19 pandemic. There may be common elements between these types of activities, and they may draw on the same resources and infrastructure. Non-research activities, such as surveillance and emergency non-research use of unproven interventions, and research activities must all be undertaken in an ethical manner as components of emergency response. However, care is needed to distinguish between non-research public health activities and research, because research often has considerations and requirements for its ethical conduct which are distinct from non-research public health activities. Research aims to produce generalizable knowledge, and mechanisms such as participant consent and independent ethics review aim to ensure that the rights and interests of research participants are respected. Ensuring that research and non-research activities are appropriately distinguished can additionally promote proper coordination of such activities, and increase trust and social accountability in pandemic responses. Consequently, it is important to distinguish between these different activities on the basis of their primary aim, and to consider whether their implementation is justifiable, based on their aims and the relevant ethical framework for each type of activity, and how they are coordinated as part of the larger collective activity of emergency response and management. Complex questions arise about how the different stakeholders involved in decision-making should make valid and justifiable decisions about whether the response activity is research or non-research. The cases in this chapter invite consideration about how such decisions should be made, and their implications, in the context of applications to conduct retrospective research into the outcomes of emergency uses of unproven interventions outside clinical trials, and of characterising antibody-testing initiatives and systematic data collection activities as surveillance or research.

4.1 Introduction

A public health response to an outbreak, epidemic or pandemic (OEP) involves a heterogeneous set of activities that aim to address the threat to public health posed by an infectious pathogen. These activities include non-research activities, such as prevention and control interventions and surveillance, and research activities. Prevention and control interventions can be based on the information and findings produced by surveillance and research, which are forms of data collection activities for different purposes.

Non-research public health activities – commonly called “public health practice” – are routinely implemented in emergency and non-emergency situations. Care is always needed to determine the boundaries between non-research public health activities and research (see Table 4.1). This is because research, including its subset of public health research, has particular considerations and requirements for its ethical conduct which are distinct from non-research public health activities (Otto et al. 2014). Non-research public health activities aim at protecting and promoting the health of a given population and are guided by considerations such as health maximization, mitigation of health inequities, and proportionality, i.e. interventions that infringe on individual rights and interests should be proportional to the relevant threat and risks, and expected health benefits. Research aims to produce generalizable knowledge, and mechanisms such as participant consent and independent ethics review aim to ensure that the rights and interests of research participants take precedence over the production of generalizable knowledge.

Table 4.1 Definitions

As the case studies in this chapter show, the boundaries between research and non-research response can easily and quickly blur during a public health emergency such as the COVID-19 pandemic. One reason for this is the existing or potential common elements between these activities. For example, surveillance and research may apply similar methodologies of systematic data collection, analysis, and dissemination, and can raise similar ethical issues, such as the exposure of individuals to privacy and data protection risks.

Another reason for the blurring of boundaries is that resources and infrastructures set up for research can be co-opted to support non-research public health activities, and vice-versa. For example, existing databases and biorepositories for research on other infectious diseases were used for surveillance purposes during the COVID-19 pandemic (Doerr and Wagner 2020). Research ethics committees (RECs) or institutional review boards – independent ethical oversight mechanisms for research – may also be used to review the emergency provision of unproven medical interventions outside of clinical trials, in accordance with the MEURI (Monitored Emergency Use of Unregistered and Investigational Interventions) ethical framework advanced by the World Health Organization (WHO) (PAHO 2020; WHO 2018) (See Table 4.2).

Table 4.2 The MEURI framework

This chapter considers a central theme that runs through the four case studies: the ethical importance of clear boundaries between research and non-research activities – with focus on surveillance and non-research use of unproven interventions – conducted in response to an OEP. This raises two issues. The first is the challenge of identifying whether an activity constitutes research or not (see Table 4.2). This is not a new issue (Barrett et al. 2016; Otto et al. 2014; Taylor 2019; WHO 2015), and has been clearly recognized in previous OEP emergencies, such as the Zika outbreak in Latin America (PAHO 2016), as well as in non-OEP situations (Beauchamp and Saghai 2012; Mastroleo and Holzer 2020). The second issue is the need to coordinate non-research activities with research activities for an effective and ethical OEP response. This invites the question of whether a non-research activity ought to be conducted as research (and thus be justified or guided by a different set of ethical considerations), and vice versa. This chapter will examine these issues and provide key considerations for addressing them as they arise in the contexts of the case studies.

As an important preliminary consideration, it should be noted that there are differing positions on the boundary between research and non-research activities as part of an emergency response to an OEP. One position is that the boundary is not always clear and not all activities within an OEP response can be classified neatly as either research or non-research, for example the monitored use of unproven interventions outside of clinical trials, which has elements of both practice and research. So for activities that lie in the so-called ‘fuzzy middle’, the focus should be on identifying and addressing the ethical issues, rather than trying to place them into one category or the other. The downside of such a position is that the responsible agent of the activity and the relevant authority would likely find it challenging to determine what ethical standards or safeguards to uphold, or the ethical purpose of procedures like consent and ethics review. A further potential effect is that policymakers may set an arbitrary set of ethical or regulatory rules for some activity without adequate justification. Alternatively, they may let the responsible agents figure out what to do by themselves in an uncoordinated manner, which risks undermining an effective and ethical response to a public health emergency.

The second position on the boundary is that an activity that has both research and practice components and multiple aims can be categorized as either research or not according to its primary aim, which gives the activity its ethical character and orients its requirements. Insofar as a reasonable national response to an OEP emergency depends on appropriate ethical regulation of activities and their transitions, which in turn depends on how they are classified, such an activity ought to be classified as either a research or non-research activity rather than be left in the fuzzy middle. This also applies to monitored emergency use of unproven interventions outside of a clinical trial, which one of us have argued should be classified as an emergency care practice according to its primary aim (as discussed below). “Fuzziness” or “grey areas” may be cases where individuals and institutions are confused about (1) the primary aim of an activity, (2) its place in the overall response to an OEP, (3) how to design that activity according to its primary aim, or (4) if the design of an activity is appropriate given the classification of the activity and its multiple aims (which ought to be subordinated to the primary aim). These issues could be resolved by an appropriate mechanism of review by a national bioethics committee, or expert consensus backed by a competent national authority in charge of the emergency response. In the case of international public health emergencies, such a mechanism should draw on guidance from international documents and expert committees convened by international health authorities (e.g. WHO, Pan American Health Organization (PAHO)) where national states participate as members. The discussion in this chapter is based on the second position, which we support.

4.2 The Research–Practice Distinction

Research involving human subjects, including during public health emergencies, has to uphold appropriate scientific and ethical standards (London and Kimmelman 2020; WHO 2020a) by observing requirements such as scientific validity and value, social value, independent ethics review, privacy and confidentiality, the right of subjects to withdraw from the research, and informed consent (Emanuel et al. 2008).

Case 4.1 raises the issue of whether consent should be waived with respect to a retrospective study on the clinical outcomes of emergency use of convalescent plasma for treating COVID-19. REC approval of consent waiver, which typically applies to secondary research using individually identifiable information, depends on the satisfaction of some or all of the following considerations: the study meets some threshold of serving the public good or public interest; it is necessary to use individually identifiable information; it is impracticable to obtain informed consent; the study presents no more than a minimal risk to the participants; and the waiver will not adversely affect their rights and welfare (Schaefer et al. 2020). Adherence to research ethics requirements and standards ensures that use of the information and bodily materials of individual persons to achieve research goals will not take precedence over their rights and interests, which is important for safeguarding public trust in research as a scientific endeavour.

In comparison, although individual rights and interests should be respected, it is sometimes necessary, and legitimate, for non-research public health activities to override these rights and interests in order to fulfil the public health mandate of protecting and promoting the collective health of a community. Consider Case 4.2 which discusses the ethical justification for decisions on the return of individual antibody test results by a public health surveillance testing initiative and two seroprevalence research initiatives. Broadly, assuming that the tests used are validated and highly accurate, public health practitioners conducting surveillance testing are justified in returning individual test results for public health reasons (e.g. as the basis for restriction of movement to prevent transmission), even if there is no prior consent. In comparison, researchers’ ethical obligation to disclose individual test results in the context of seroprevalence research (as well as many other types of research) would depend on whether they (and RECs) deemed that the result or risk identified was medically actionable or individually meaningful, and whether they had obtained informed consent, so as to respect participants’ right not to know (Downey et al. 2018). Other issues include whether there are resources to return individual results in an ethically responsible and feasible manner (Wong et al. 2018), and how false positive and negative results should be dealt with to minimize harm.

The ‘research–practice’ distinction and how we identify a proposed systematic data collection activity as one or the other are therefore ethically important, as they imply a shift in ethical commitments, standards, and requirements. As Case 4.2 and Case 4.3 suggest, and as is the practice in many settings, the classification of a systematic data collection activity as public health surveillance would typically mean that its ethical conduct was not contingent on prior independent ethics review. Conversely, determining that such an activity was research would mean there was a need to submit a formal protocol for REC review.

The normative line between research and practice in terms of types of data collection activities that need to or need not adhere to ethical safeguards such as informed consent and independent ethics review does not apply in every instance. For example, monitored emergency use of unproven interventions outside of clinical trials using a MEURI protocol requires informed consent from the recipients of the interventions and review by an REC or some other qualified ethics committee (see Table 4.2). Some scholars have also argued for ethical oversight of public health surveillance activities (Fairchild and Bayer 2004). Consistent with such thinking, the WHO endorses the establishment of an independent and impartial ethical oversight mechanism for public health surveillance systems (WHO 2017), while the PAHO states that surveillance activities, especially in the context of a public health emergency, should undergo some form of ethical oversight. WHO and PAHO are in agreement that ethical oversight of public health surveillance should not mimic approaches to research ethics oversight. The issue of ethical oversight of public health surveillance for OEP is discussed further below.

Regardless of the argument that public health surveillance should undergo some form of ethical oversight (or at least receive ethical guidance to ensure that they are conducted ethically), some methods or criteria are necessary to distinguish data collection activities carried out as research from non-research public health activities. This is to ensure adherence to any existing ethical requirements or regulations specific to these different activities, and to prevent their conflation, which could undermine the overall public health response to an OEP.

4.3 Locating the Distinction in the Primary Aim

Case 4.3 presents the question of whether a public health survey – deemed “necessary to inform planning for pandemic response” – should be considered a surveillance or a research activity. The common way to consider whether a public health activity ought to be classified as research or non-research is with reference to its primary aim. As mentioned, whereas the primary aim of a non-research activity is to prevent/reduce disease or improve health, the primary aim of research is to produce generalizable knowledge. In the context of health research, this has been defined as “theories, principles or relationships, or the accumulation of information on which they are based related to health, which can be corroborated by accepted scientific methods of observation and inference” (CIOMS 2016: p. xii). Basing the boundary between research and public health practice on “primary aim” may not make it clear in some cases. It could be argued that the primary aim of research in response to an OEP emergency is to produce generalizable knowledge precisely to develop the means of preventing, controlling or treating the disease that triggers the emergency (WHO 2015, see p. 23).

One way to make the demarcation clearer, and to better establish the primary aim of a proposed systematic data collection activity, is to consider the actors involved and their ethical duties qua the role they occupy, as well as the target beneficiaries of the activity (Taylor 2019). In brief, public health authorities and practitioners should design and conduct activities that promote and protect the collective health and safety of the community within their jurisdiction as their primary ethical duty. The potential use of the data to benefit communities outside of their jurisdiction is incidental or at most a secondary concern. In contrast, although researchers have an ethical duty to protect research participants, they also have a duty to ensure that their research holds the prospect of scientific and social value that will outweigh the risks and burdens participants undergo and the resources used. Scientific value and social value can be anticipated if the study is designed to produce knowledge that could benefit others in the future. Although the research process could benefit the participants and the knowledge produced could benefit the community from which they are drawn, the research should be designed to yield data and conclusions that could be generalized for use by those beyond the participating community to maximize scientific and social value.

Thus, it has been contended that “when the intent of the systematic public health data collection is to benefit those beyond the borders of the local jurisdiction” (Taylor 2019), it should be classified as research, even if the activity is conducted by a public health authority. Using “intent” or primary aim to distinguish research activities from non-research public health activities underscores the importance of research as a component of OEP response, as the scientific and social value of the knowledge it produces could apply to communities in other settings or to the global community.

4.3.1 Experimentation

For health interventions, an important consideration for what their primary aim ought to be is whether the intervention is experimental. Experimentation may be defined as “exposure of an individual or community to an activity not yet proven effective (i.e., not yet standard practice)” (Taylor 2019). Typically, non-research health interventions are standard measures with a proven history, or they are backed by scientific evidence of effectiveness in preventing disease and promoting individual health or the health of a community, and the intended known benefits outweigh the potential risks. Lack of or insufficient knowledge on the safety, effectiveness, and risk-benefit balance of a health intervention, and the potential of increasing certainty and understanding of these elements through research methods, are reasons for providing that intervention through research and its ethical safeguards. There are exceptional situations, however, where it is justified to provide experimental or unproven interventions outside a research context.

For instance, in the context of a public health emergency involving a novel pathogen where mortality is high and no proven treatments or prophylaxes exist, unproven interventions may be ethically provided on a case-by-case basis with the intent to save their lives or reduce their suffering through different non-research routes, such as off-label use, expanded access, and MEURI (Lysaght et al. 2022). Unproven interventions may also be made available to a given population to realize some public health goal through MEURI, or country-specific mechanisms for emergency use authorization to facilitate the availability and use of medical countermeasures (“unapproved medical products, or unapproved uses of approved medical products” – Krause and Gruber 2020). In general, the risk-benefit ratio should be favourable, and the conditions specific to each pathway that permit the ethical emergency use of an unproven intervention outside of clinical trials to benefit individuals or groups must be met.

Despite the availability of criteria to determine when its implementation is ethically justified, the MEURI framework can be seen as intrinsically complex. Although MEURI is defined as a non-research activity aimed at offering individuals or groups access to an unproven intervention that might benefit them, it calls for a contribution to the production of evidence through systematic collection, monitoring and dissemination of data (PAHO 2020:5). It is unclear what “production of evidence” means and what the evidence should be used for. Statements by WHO, such as “physicians overseeing MEURI have the same moral obligation to collect all scientifically relevant data on the safety and efficacy of the intervention as researchers overseeing a clinical trial” (WHO 2016, p. 36) may invite the view that “production of evidence” just is production of generalizable knowledge. If so, it suggests that MEURI is not that different from research, or is a form of observational research even though it is not a controlled clinical trial.

To set a clear boundary between monitored emergency use and research, one of the authors of this chapter (Voo) and his colleagues have argued that the aim of monitored emergency use is to protect the “safety of the patient(s) receiving the [unproven] intervention, with the ancillary benefit of collecting data on safety and effectiveness that could be used to inform clinical trial designs (e.g., dosage, patient population, outcome measures, etc)” (Lysaght et al. 2022, p. 336). The primary aim of data collection, monitoring and dissemination therefore is to directly benefit patients, even if it may (indirectly) contribute to the production of generalizable knowledge by providing data and evidence to inform the design of any subsequent clinical trial on the unproven intervention. In other words, “primary aim” provides a basis for distinguishing between research and monitored non-research emergency use of unproven interventions as an emergency care practice.

In sum, “primary aim” is, arguably, the central concept for classifying a systematic data collection activity as research or non-research, and this would be shaped by considerations such as the actors involved, the targeted beneficiaries, and whether the intervention is sufficiently proven. As “[e]mergency circumstances can lead to a blurring of limits between public health practice and research, both because of time constraints and because this limit is sometimes genuinely difficult to define” (Calain et al. 2009), it would be good practice to implement a third-party mechanism such as a national ethics committee – which appears to be used in Case 4.3 – to adjudicate on cases when there is confusion between the boundaries of research and practice (PAHO 2016).

4.4 Should Non-research Activities Be Conducted as Research Instead?

Scarce resources should be used to shore up the health system and non-research public health response during an emergency like COVID-19 to prevent disease, and loss of life and suffering. It is important to recognize, however, that research is also a key aspect of OEP response because certain critical questions can only be adequately answered by research methods (London and Kimmelman 2020). For example, randomized controlled trials to establish causal relationships between interventions and effects, in conjunction with other available knowledge, remain the primary way to prove or disprove the quality, safety and efficacy of medical products accepted by national regulatory agencies (Khadem Broojerdi et al. 2020). Thus, although many activities are legitimately conducted as non-research public health response during an emergency, it might be more justifiable to conduct certain activities as research to generate the evidence for proving or disproving hypotheses and propositions related to the infectious pathogen and prevention, control and treatment measures, which would also assist with preparedness for future similar emergency situations.

Public health and medical practitioners may however not initiate their activities as non-research activities despite good scientific and ethical reasons to conduct them as research instead. As suggested by Case 4.3, one reason why those involved in public health response may prefer to classify a data collection activity as surveillance and not research is the concern that research ethics oversight would impede the activity. Just as research should not unnecessarily impede emergency response, research ethics review should not unnecessarily impede research from being carried out, especially when it is a key component of emergency response.

Since 2008, the WHO has recommended various mechanisms to facilitate rapid and robust REC review for research during OEP emergencies (WHO 2010, 2020b) (see Chap. 6). Despite the implementation of rapid ethics review, public health practitioners may prefer to classify certain public health response activities as practice even though they could potentially be classified as research, because approval may still be stalled as a result of “substantive ethical concerns” by the REC (see Case 4.3). Or, because certain requirements, such as informed consent, would not be waived if the activity was classified as research, which could reduce their efficiency and effectiveness in achieving the public health goals. Another reason could be the belief that professional ethical expectations and best practices in public health are adequate for the protection of individual rights and interests and for the implementation of ethically sound practices (Lee 2019). Whether public health surveillance should undergo ethical oversight or would benefit from it, especially in an OEP emergency, may depend on the socio-cultural and political context in which the surveillance was conducted, and the agility and responsiveness of the oversight mechanism (Lee 2019).

In the bid to save individual patients or achieve some public health goal, such as reduction of infection incidence and disease burden, unproven interventions may be provided to specific individuals or populations through non-research pathways at the same time as they are being investigated in controlled clinical trials. As described in Case 4.4, this may cause confusion among non-research recipients, as well as research recipients and other stakeholders, about whether the intervention is proven or unproven. Also, it may pose complex questions; for example, what comprises sufficient evidence to justify monitored emergency use of unproven (medical) interventions outside clinical trials and who is responsible for establishing this? (PAHO 2020). (MEURI access should be provided on an exceptional basis during public health emergencies when proven interventions are absent or unsatisfactory; reasons should be given as to why a clinical trial cannot be initiated immediately instead; a favorable risk-benefit balance should be established by a qualified scientific advisory committee based on sufficient preliminary evidence of safety and efficacy; and that such use of unproven interventions do not unduly threaten other essential activities of prevention and management of a public health emergency, including research (WHO 2020a, b, Section 2.3)). In an age where the spread of information is amplified by social media and other digital platforms, permitting an experimental or investigational product to be used as a clinical or public health intervention may create a widespread perception that it is already a product with a proven safety and efficacy profile, which may inhibit the development of proven interventions through research (e.g. by increasing pressure for non-trial access and impeding trial recruitment). Hence, the risk of any type of unmonitored access (e.g. unmonitored “off-label” use or “compassionate use”) to unproven interventions is that it may undermine the public health response to an OEP by contributing to the widespread uncontrolled use of unsafe or inefficacious unproven interventions (CIOMS 2016, Guideline 20), and result in more harm than good.

It is thus important to coordinate research and non-research public health activities so that the former is not undermined by the latter and can be effectively carried out to generate robust scientific evidence to inform and formulate responses to a public health threat. For example, regarding Case 4.3, one could argue that it is more effective and ethically appropriate for the public health survey to be conducted as research so that data collection is separated from the goal of active case detection.

Case 4.1 prompts the question of whether a prospective study on clinical outcomes of convalescent plasma treatment of COVID-19 patients should have been conducted instead of a retrospective study, or whether the convalescent plasmas should have been provided through a MEURI protocol (if requirements for MEURI had been met). The data collected through MEURI could have been used to support (or decide against) clinical trial initiation or to inform the design of such a trial. Providing the treatment through either research or MEURI would have required informed consent (unless there were good reasons against this, for example, patients did not have the capacity to give consent, in which case proxy consent could have been obtained). The extent to which patients should be given different information depending on whether they had the treatment through research or through MEURI is an interesting question.

For Case 4.4, the activity of providing the COVID-19 investigational vaccine to health-care workers (HCWs) could become part of the ongoing Phase II trial but its exclusion of those with current or previous SARS-CoV-2 infection would likely result in the non-participation of many HCWs, given their high risk of exposure to the virus and lack of vaccination. This raises the question of whether the trial’s inclusion/exclusion criteria are justified, which is a matter of fair subject selection and depends primarily on the scientific aims of the trial (Emanuel et al. 2008). Given that the primary public health aim is to protect HCWs, however, it is important to consider whether it is ethically justifiable to provide the investigational vaccine to these workers through emergency use authorization (EUA). Whether it is justifiable to do so will depend on whether there is adequate interim trial data on its safety and efficacy (as determined by the relevant regulator) to support a favourable risk-benefit assessment. This is a key consideration for emergency use authorization, as is the potential of the medical product to prevent, diagnose or treat serious or life-threatening diseases or conditions (Singh and Upshur 2021). Again, an independent scientific and ethical oversight system could be involved in the assessment of the preliminary evidence as well as the risks and benefits of this non-research activity, so as to increase confidence that the vaccine is unlikely to cause net harm if offered under an emergency use authorization (in the US) or other form of monitored emergency use. In any case, “to minimize the risk that use of a vaccine under an EUA will interfere with long-term assessment of safety and efficacy in ongoing trials, it will be essential to continue to gather data about the vaccine even after it is made available under the EUA” (Krause and Gruber 2020).

4.5 Conclusion

Non-research activities, such as surveillance and emergency non-research use of unproven interventions, and research activities must be undertaken in an ethical manner as components of an OEP emergency response. To ensure this, it is important to identify these different activities on the basis of their primary aim, and to consider whether their implementation is in itself justifiable, based on their aims and the relevant ethical framework for each type of activity, and how they are coordinated as part of the larger collective activity of the OEP emergency response and management. How to make valid and defensible decisions on the type of response activity – whether research or non-research – is a complex question with different stakeholders involved in decision making. The aim is to ensure that research and non-research activities are appropriately distinguished, to ensure the proper coordination of such activities, and to increase trust and social accountability in OEP response.

Appendices

Case 4.1: Use of Convalescent Plasma in Severely Ill COVID-19 Patients

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

Keywords

Boundaries between research, surveillance and clinical care; Data protection, access and sharing; Consent; Treatment repurposing; Emergency Use Authorisation

SARS-CoV-2 is responsible for a severe acute respiratory syndrome, which can cause death, particularly in more vulnerable people. The use of human convalescent plasma was considered as a potential treatment for COVID-19 (Casadevall and Pirofski 2020). While the United States Food and Drug Administration (FDA) had not approved its use for this purpose, it could be provided initially under the expanded use programme and subsequently through emergency use authorization as an investigational product (US Food and Drug Administration n.d.).

Human blood plasma has been used in restricted contexts to treat other viral diseases for which there are no established treatments. Previous studies with human plasma for treatment of Hantavirus cardiopulmonary syndrome showed that it appeared to be safe and able to reduce the fatality rate (Vial et al. 2015). Likewise, during the Ebola epidemic, the World Health Organization determined that, in the absence of other proven treatments, convalescent plasma could be authorized for “monitored emergency use” as an “unregistered and experimental intervention” when treating people with Ebola virus disease (WHO 2015).

In June 2020, a research ethics committee (REC) in South America, received a request to review a retrospective research protocol aimed at studying the use of convalescent plasma as a potential treatment for severe COVID-19 pneumonia. The researchers requested a waiver of informed consent for obtaining clinical data from the patients´ health records, because they considered it to be a protocol which aimed to evaluate a clinical practice, not a new therapeutic approach. At the time of the request, at a country level, there were a small number of ongoing clinical trials investigating the efficacy and safety of the use of convalescent plasma. In these cases, REC approval had been obtained prior to the administration of plasma, and both donors and recipients (or their representatives) of plasma had consented to participate in the trial. However, other institutions, such as the clinical centre requesting ethical approval for this retrospective trial, had adopted the administration of plasma as a clinical practice rather than an experimental intervention. Consequently they had not complied with guidance for the emergency use of unproven interventions outside of research, including the requirements for prior ethical review and informed consent (PAHO 2020). While plasma donors had given informed consent to donate their plasma for treatment, the patients who received convalescent plasma did not give informed consent to receive an unproven intervention, or consent for their clinical data to be used in research.The REC discussed the scope of its review: did the research encompass the administration of human plasma as an investigational product, or was it limited to the retrospective analysis of a clinical practice study?

Questions

• 1. In a pandemic, when emergency use authorizations are in place, are there morally significant differences between the prospective use of a medication under emergency use authorization, and a retrospective analysis of a clinical practice? What are the reasons for your views?

• 2. Given guidance for emergency use of unproven clinical interventions outside of trials, was it ethically acceptable for researchers to characterise their use of convalescent plasma as a clinical practice to be retrospectively evaluated? Why?

• 3. In this case should the REC focus on the ethical issues related to using an unproven intervention in a pandemic or on the request to access and analyse retrospective clinical data? Why?

• 4. Should a request for a waiver of informed consent to access the clinical data be granted in this situation? Why?

References

• Casadevall A, and L. Pirofski. 2020. The convalescent sera option for containing COVID-19. Journal of Clinical Investigation 130(4): 1545–1548.

• PAHO. 2020. Emergency use of unproven interventions outside of research ethics guidance for the COVID-19 pandemic. Pan American Health Organization. https://iris.paho.org/handle/10665.2/52429.

• US Food and Drug Administration. n.d. Recommendations for investigational COVID-19 convalescent plasma. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma.

• Vial, P.A., F. Valdivieso, M. Calvo, M.L. Rioseco, R. Riquelme, A. Araneda, V. Tomicic, J. Graf, L. Paredes, M. Florenzano, T. Bidart, A. Cuiza, C. Marco, B. Hjelle, C. Ye, D. Hanfelt-Goade, C. Vial, J.C. Rivera, I. Delgado, and G.J. Mertz (Hantavirus Study Group in Chile). 2015. A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome caused by Andes virus. Antiviral Therapy 20(4): 377–86.

• WHO. 2015. Ethics of using convalescent whole blood and convalescent plasma during the Ebola epidemic: Interim guidance for ethics review committees, researchers, national health authorities and blood transfusion services. Geneva: World Health Organization. https://apps.who.int/iris/handle/10665/161912.

Case 4.2: COVID-19 Antibody-Testing Initiatives in a European Country

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

Keywords

Boundaries between research, surveillance and clinical care; Researcher roles and responsibilities; Researcher roles and responsibilities; Return of results

In 2020, a number of different programmes involving testing for SARS-CoV-2 antibodies were established in a European country.

A major biobank invited existing participants to provide blood samples, which would be tested for antibodies to provide data about the extent of previous infection in different parts of the country. This study was subject to standard ethical review processes. Results were not available to participants, on the grounds that this was a research programme and was established to study results at population and not individual level. As such it was not intending to offer a clinical or public health service, and at the time, the biobank took the view that feedback outside of the normal clinical setting would be of questionable value, and might even be harmful.

At the same time, health authorities in the country established an antibody-testing programme. This programme had a similar aim: to provide information on the prevalence of COVID-19 in different parts of the country and improve understanding of how the disease was spreading. This was not badged as research and did not undergo ethical review. Antibody testing was offered initially to health-care workers, and then to patients who were having a blood test for other purposes. Results regarding the presence or absence of COVID-19 antibodies were shared with participants.

Running alongside these two initiatives, a nationwide study of a sample of private households was run by the national statistical authority, in order to track levels of both current and past COVID-19 infection (using nose/throat swabs and blood samples respectively). This was considered to be research and was subject to ethical review. Participants were sent their results around a week after testing.

Questions

• 1. What implications does the pandemic context have for arguments for and against rapidly sharing antibody test results with participants in both research and public health surveillance contexts?

• 2. What are the ethically significant differences between the initiatives identified as research, and the initiative identified as public health surveillance?

• 3. Are these differences likely to be seen as relevant from the perspective of the participants taking part? Why?

• 4. Could these differences in approach be justified by technical reasons, for example relating to the likely accuracy of individual results? If so, how could this be handled so that participants feel informed and respected?

Case 4.3: Competing Priorities Under Pressure: Government Collaboration with Academic Institutions

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

Keywords

Boundaries between research, surveillance and clinical care; Researcher roles and responsibilities; Ethical review; Safety and participant protection; Consent; Privacy and confidentiality

Political leaders and the public health agency in a small lower-middle-income country implemented urgent measures to contain the acute spread of COVID-19, including a number of social and economic restrictions. These measures were developed in consultation with a team comprising academic, political and public health leaders. In response to an increase in COVID-19 cases, the government decided that a door-to-door household survey of COVID-19-related symptoms and behaviours (e.g. adherence to non-pharmaceutical interventions) was necessary to inform planning for the pandemic response. The president of the country announced the initiative on television.

A member of the survey team contacted the national research ethics committee to discuss whether research ethics review should be required. The survey team had expressed differing views in internal discussions, with the majority holding that the survey did not require review because they conceptualized the project as a government-endorsed public health surveillance activity.

Moreover, the survey team viewed the research ethics review process as having the potential to unnecessarily delay the collection of information urgently needed to contain the pandemic. The team held these views even though the ethics committee had developed and publicized a rapid review process 10 months previously, at the start of the COVID-19 outbreak. The process had facilitated a number of reviews on an accelerated schedule for COVID-19-specific research, as well as on-going studies requiring amendments to accommodate increased safety measures to minimize risks of SARS-CoV-2 transmission. During the course of the rapid review programme, some proposals had been quickly actioned; others had taken longer, owing to both substantive ethical concerns and operational challenges for the ethics committee.

As the survey team had not submitted a protocol to the ethics committee, the proposed procedures for informed consent and other safeguards to protect the rights and well-being of participants were not clear. The conversation between the survey team and ethics committee revealed a number of potential ethical concerns that merited consideration. There was a possibility that the survey data collectors would be asked to inform public health authorities if they observed survey participants showing signs of COVID-19. However, the data collection protocol for the survey did not include prior informed consent, raising the possibility that persons answering a knock at the door might be reported to government health authorities, an action that could result in involuntary isolation at a quarantine facility. Political leaders emphasized publicly that the door-to-door contact would provide the opportunity to identify people with suspected COVID-19 who potentially posed risks to others or were at risk themselves. In the context of the pandemic the survey would therefore not just collect data, but also potentially act as a mechanism to limit spread of infection, with a consequent impact on individual liberties.

Further, law enforcement and military personnel were assisting in both the humanitarian and enforcement components of the public health response to the pandemic. Although soldiers and police would not be conducting the survey directly, they would provide security for the survey team and might be visible while survey data were being collected.

Questions

• 1. Should a survey of this type be considered a public health surveillance measure or a research study? Why?

• 2. How should research ethics committees respond when they have been informally notified of a survey that raises concerns but are advised that it will not be submitted for review due to the urgency of conducting it?

• 3. How should public health surveillance activities be better coordinated with (or differentiated from) research efforts in the context of a pandemic, especially when the priorities of research ethics committees (e.g. ensuring the ethical conduct of research, including protecting the interests of participants) and public health authorities (e.g. containing spread of infection) might conflict?

• 4. What concerns might you have regarding protections for survey respondents in this scenario? Would the concerns change if the survey was seen as purely a public health initiative to inform pandemic responses without a research component?

Case 4.4: Vaccine Research or Rollout?

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

Keywords

Boundaries between research, surveillance and clinical care; Research design and adaption; Risk/benefit analysis; Vulnerability and inclusion; Vaccines

In a South American country, the government was making an effort to combat the advance of COVID-19 in its territory. It was the first country to carry out a clinical investigation of a new recombinant vaccine for the prevention of COVID-19.

A clinical trial aimed to assess the vaccine’s efficacy against the numerous variants of the SARS-CoV-2 virus circulating in the country. The vaccine had received emergency use authorization and the Phase II study was conducted in the main cities of the country. To reach recruitment objectives, the population was called on to volunteer for the study. All participants would receive free medical care, as well as private medical insurance, and reimbursement for food, transportation and medical consultations. In light of these benefits, and especially the potential of gaining immunity to COVID-19, many people volunteered to join the trial. An exclusion criterion for the trial was a current or previous infection with SARS-CoV-2.

While the trial was being conducted, health authorities also authorized the rollout of the new recombinant vaccine to health-care workers. The aim was to provide protection against infection to health-care staff who were frequently in contact with COVID-19 patients and therefore playing a key role in the fight against the pandemic. In contrast to the trial participants, health-care workers were offered the vaccination even if they had previously been infected with SARS-CoV-2.

This led to questions among health-care workers about whether they were participating in a trial or being offered the vaccination as a preventative intervention. Some health-care workers were grateful to be the first to receive the vaccine, since they were most likely to be exposed to infection. However, others thought the opposite, noting that as the Phase II trial was still being conducted, the vaccine’s safety and efficacy were not proven. For this reason, they opposed receiving the experimental vaccine.

Questions

• 1. During the Phase II trial is it acceptable to present this COVID-19 vaccine as an intervention to protect health-care workers? Why?

• 2. If exposure to SARS-CoV-2 infection is an exclusion criterion in the Phase II trial, is it ethical to offer the vaccine to health-care workers (who are likely to have been exposed to infection)? Why?

• 3. Are there conditions under which it would be ethically acceptable for a COVID-19 vaccine trial to have inclusion criteria restricting recruitment to health-care workers? Why?

• 4. Is it acceptable for health professionals to refuse the experimental vaccine, given the contact they have with vulnerable patients? Why?