Ethics Review Challenges

Abstract

In the context of a public health emergency it is imperative to conduct research studies that will produce evidence rapidly while upholding ethical standards. The Ebola and Zika outbreaks highlighted the importance of devising agile processes for ethics review in emergencies, and international research ethics guidelines stress the duty to depart from standard processes for ethics review in emergency circumstances. However, before the COVID-19 pandemic it was not entirely clear what emergency procedures should look like. An additional challenge is that while the same substantive ethical standards apply in emergency and non-emergency settings, deciding what these standards entail in the specific circumstances of a pandemic may be difficult. During the COVID-19 pandemic, challenges included identifying thresholds of social and scientific value, along with duties towards research participants, given the absence of therapeutic options; assessing continually changing risk–benefit profiles of studies, given rapidly emerging new evidence; developing appropriate informed consent processes, given lockdown scenarios; and even addressing the ethics of offering unproven interventions outside research settings. Additional issues raised during epidemics include devising feasible and meaningful community engagement strategies, mechanisms to ensure fairness in the distribution of the benefits that may result from research, and equitable and effective data-sharing plans that will inform pandemic response. Learning from these procedural and substantive challenges encountered in the ethics review of COVID-19 research is important for enhancing ethics preparedness for future emergencies. It can also potentially contribute to improving the ethics review of research in non-emergency circumstances. The seven cases in this chapter highlight ethical issues associated with ethics approval of multi-centre studies in pandemics, the need for careful consideration of the social and scientific value of research and challenges encountered when interventions are being transitioned from research to rollout, and issues that can arise when existing regulations and policies may limit capacities to appropriately adapt research to pandemic contexts.

6.1 Introduction

Research is an essential component of the public health response to an emergency. We need knowledge in order to find safe and efficacious interventions to help us understand, prevent, diagnose and treat emerging diseases, and overall to guide the public health response. It is imperative to conduct research studies that will produce evidence rapidly while upholding ethical standards.

However, conducting research in emergency settings is challenging. Some challenges pertain to the process of ensuring rigorous yet rapid ethics review during emergencies. Ethics review by an independent research ethics committee (REC) aims to ensure the ethical conduct of research with human participants. While obtaining ethics approval before the start of a study is a requirement that must not be bypassed during health emergencies – and doing so is tantamount to conducting research unethically – RECs should streamline their processes in order to conduct ethics review in a timely manner during a pandemic. Previous public health emergencies of international concern (PHEIC), like the Ebola and Zika outbreaks, highlighted the importance of devising agile processes for ethics review in emergencies, and the 2016 guidelines published by the Council for International Organizations of Medical Sciences (CIOMS) stress the duty to depart from standard mechanisms for ethics review in emergency circumstances (CIOMS 2016). However, before the COVID-19 pandemic it was not entirely clear what emergency procedures should look like.

A different set of challenges pertains to the ethics analysis conducted by RECs when reviewing health emergency research protocols. While the same substantive ethical standards apply in emergency and non-emergency settings, as stressed in the CIOMS guidelines and other guidance documents (CIOMS 2016; PAHO 2016, 2020b, c, f; WHO 2016, 2020a), deciding what these standards entail in the specific circumstances of a pandemic may be difficult. During the COVID-19 pandemic, challenges included identifying thresholds of social and scientific value, along with duties towards research participants, given the absence of therapeutic options; assessing continually changing risk–benefit profiles of studies, given rapidly emerging new evidence; developing appropriate informed consent processes, given lockdown scenarios; and even addressing the ethics of offering unproven interventions outside research settings.

Learning from these procedural and substantive challenges encountered in the ethics review of COVID-19 research is important for enhancing ethics preparedness for future emergencies. It can also potentially contribute to improving the ethics review of research in non-emergency circumstances.

6.2 Challenges in the Ethics Review Processes

During the COVID-19 pandemic, several guidance documents about ethical COVID-19-related research involving human subjects were issued to guide national authorities and RECs during the health emergency (PAHO 2020b, c, f; WHO 2020a, b). The first and most important task identified in these documents was for countries to establish a strategy for the organization of ethics review and oversight that was best suited to their context. This was to be undertaken with the aim of avoiding duplication of effort, preventing RECs from becoming overwhelmed, and developing mechanisms for coordination and communication between the relevant research stakeholders. For example, the relevant authorities could decide to create an ad hoc committee tasked with the conduct of ethics review and the oversight of COVID-19 research, or designate an existing REC of a national entity to be responsible for the review of these protocols. Another option could be to task one or more institutional RECs with the review of (certain types of) COVID-19 research (PAHO 2020c, 2022). Indeed, several countries rapidly implemented these strategies and, overall, international guidance to accelerate the ethics review of COVID-19 research (ICMR 2020; Palmero et al. 2021; PAHO 2022).

It is important to consider that any adopted strategy will need to be supplemented by “emergency mode” operating procedures in order to ensure that the RECs tasked with the review of COVID-19 protocols conduct a rapid yet rigorous review. Such procedures include tight deadlines for reviews, virtual meetings, electronic submission of research proposals, the inclusion of additional members and subject experts, and mechanisms for coordination and communication between RECs, investigators and authorities, among others (PAHO 2020c, f, 2022; WHO 2020b).

The difficulties that can arise in the absence of planning and of establishing a national strategy to organize and streamline ethics review and oversight processes are illustrated in Cases 6.1 and 6.2. As shown by both cases, this is of special relevance in the case of multi-centre studies because the involvement of several RECs without rapid and flexible operating procedures or clear mechanisms of coordination and communication can result in practical obstacles that duplicate efforts, waste time and resources and, ultimately, result in missing valuable research opportunities.

6.3 Challenges in the Ethics Analysis of Health Emergency Research

Ethics review of emergency research proposals must adhere to existing national and international ethical standards. However, RECs face several challenges when conducting their ethics analyses because the emergency context may seem to justify flexibility where ethical standards are concerned, when in fact it should highlight the importance of increased diligence in review processes. Certainly, applying ethical standards to unusual and rapidly changing contexts, like the COVID-19 pandemic, can be challenging and requires strong capacities for ethics analysis.

Cases 6.3–6.6 illustrate some of the challenges faced by RECs when assessing the anticipated social and scientific value of research. In addition, the cases invite reflection on the challenges to the ethical conduct of research in cases where interventions have been proven safe and efficacious elsewhere and are being transitioned from research to rollout, and on the role of RECs regarding the use, outside of research settings, of interventions that have not been proven. Case 6.7 raises issues about the informed consent process during the COVID-19 pandemic, which is another component of ethics review.

6.3.1 Social and Scientific Value of Research

Despite regulatory, logistical and practical difficulties in emergency situations, research with human participants must have social and scientific value. Lack of purpose and scientific rigour may not just waste resources and effort but it is ethically problematic because participants are being exposed to risks without the prospect of future benefits, such as valuable and valid knowledge, being produced. The urgency with which knowledge is needed in emergency situations does not alter moral duties to conduct research that adheres to scientific standards. Such urgency should not be construed as permission to conduct research that is not scientifically sound or that is ethically questionable for any other reason (London and Kimmelman 2020).

During the COVID-19 pandemic, we have seen a vast amount of research conducted in an unprecedentedly short time. Yet many of the studies have small samples, unnecessarily replicate hypotheses, do not have adequate comparators, and in general, have methodological flaws that make them unlikely to produce robust evidence or even incapable of producing it (London and Kimmelman 2020; Carracedo et al. 2020). Moreover, the choice of some interventions under study does not seem justified by prior knowledge, and even interventions already known to be harmful have been studied (London 2021; PAHO 2020e; Herper and Riglin 2020) (see Chap. 3).

Cases 6.3–6.5 illustrate the need for careful consideration of the social value and scientific merits of protocols as part of the ethics review. Challenges pertaining to the soundness of the scientific justification for the research, and the acceptability of small and repetitive clinical trials that do not seem capable of producing robust evidence in a timely manner, as well as the qualifications of the research team to conduct emergency research, highlight the importance of the role of RECs in ensuring well-designed and high-quality research that can generate valuable knowledge during a health emergency.

Another crucial aspect to take into account is the fact that the social and scientific value of research is not static, and that the ethical acceptability of approved protocols can vary while the study is underway. This is especially relevant in emergency settings characterized by a rapid production of scientific evidence, as discussed in Chap. 5. In this sense, the oversight of on-going emergency research may need to be more frequent. That means, on the one hand, that researchers have a responsibility to constantly evaluate the justification for their research on the basis of the most up-to-date evidence and to make decisions regarding the conduct of their studies accordingly. And on the other hand, RECs should oversee the conduct of the study until its completion, in light of the emerging scientific evidence, in order to take appropriate measures to guarantee its continued adherence to ethical standards (PAHO 2020d, 2022).

6.3.2 Consent Processes

Obtaining informed consent from participants is necessary for all research involving human subjects conducted during a health emergency, unless an REC approves a waiver of this requirement on the basis of particular criteria, such as those established by the CIOMS guidance (CIOMS 2016).¹ In practice, several obstacles caused by the circumstances of the health emergency (e.g. isolation of patients, lockdowns) may preclude the ordinary process of obtaining informed consent and thus pose a need to consider alternative ways of doing so. Indeed, during the COVID-19 pandemic, alternative procedures were proposed (PAHO 2020c, f) and established by many national authorities and regulatory agencies (ICMR 2020; Palmero et al. 2021). For example, the use of electronic informed consent forms or other electronic means (e.g. telemedicine, phone calls, video calls, photographs, etc.) to facilitate consent processes and to contact family members or legal representatives for support or proxy consent has become increasingly widely accepted (see Chap. 9).

However, in many cases these alternative processes have not been deemed compliant with national regulatory frameworks that stipulate requirements for consent processes (e.g. an in-person process) and the documentation of research participants’ decisions (e.g. in a hard copy). Therefore, it is necessary to think about how regulatory requirements for consent processes should be addressed in emergency situations, which were presumably not taken into account when these requirements were devised. Consequently, RECs may need to be prepared to reassess the conduct of informed consent processes and suggest alternative methods. This requires RECs to understand and balance the differences between their responsibility to ensure respect for potential participants’ autonomy and the need to comply with legal requirements, some of which may even expose participants and researchers to higher risks (e.g. the possible spread of the disease through paper forms or in-person encounters). Case 6.7 raises this issue and invites us to reflect on what it is right to do when existing regulations and institutional policies may come into conflict with ethics.

6.3.3 Research in the Transition from Research to Rollout

The magnitude of research that has been conducted in response to COVID-19 has led to the rapid production of evidence on the safety and efficacy of interventions, and subsequent approvals of these interventions by different national regulatory authorities (NRAs) around the world. NRAs have often relied on emergency use authorizations (EUAs) in order to make therapeutic and preventive interventions available as soon as possible during the pandemic.

In this scenario, the conduct of research has encountered additional challenges. Some challenges pertain to the justifications for conducting research on interventions that have been deemed safe and efficacious in other jurisdictions and are being offered to the population there. Several reasons to justify research on these interventions can be conceived, e.g. to obtain more specific knowledge, which initial studies were not designed to obtain, including their performance in response to new SARS-CoV-2 variants. Arguably, an EUA highlights the need to continue conducting research, for instance to collect follow-up data for a longer period of time. Additionally, the conduct of local research in order to authorize interventions may be a national regulatory requirement, even if those interventions have been proven safe and efficacious elsewhere and authorized by other NRAs. In any case, the justification for research in these circumstances should be clearly laid out and the proposals carefully assessed, to ensure the ethical conduct of the study.

Case 6.6 illustrates the complex set of ethical challenges that can be encountered when research is conducted while the interventions under study are being rolled out as part of the delivery of care. These challenges range from the justification for these studies, to the duties towards research participants and their communities. In the context of COVID-19, there has been a global need for efficacious interventions for prevention and treatment, but these interventions have not been available everywhere at the same time. Moreover, the availability of these interventions as part of the delivery of care can hamper the capacity to conduct research (such as when a study entails randomization) even if such research is associated with significant social and scientific value and could otherwise be conducted ethically. RECs must conduct a careful assessment of these studies and may have to grapple with the ethical justification of regulatory requirements (such as bridging trials) in emergency situations. Furthermore, as Case 6.6 points out, there is a need to consider regulatory procedures that can catalyse rigorous and rapid research during emergencies, as has been done with ethics review and oversight processes.

6.3.4 Use of Unproven Intervention Outside Research Settings

Another challenge faced during public health emergencies is the exceptional use of unproven interventions outside research settings (see Chap. 4). In normal circumstances, interventions are tested in research settings to prove their safety and efficacy. In these settings, as participants are receiving interventions whose safety and/or efficacy is being evaluated, safeguards are necessary (e.g. ethics review by a REC). Once an intervention has been proven safe and efficacious, it can be offered to persons outside research settings, i.e. as a public health intervention without these safeguards.

However, during health emergencies, unproven interventions are sometimes offered outside research settings as an alternative that may benefit patients. This raises obvious concerns: the safeguards intrinsic to research settings are not available outside such settings yet people are receiving interventions whose safety and efficacy are not known. The use of unproven interventions in these exceptional contexts can, however, be ethically justified if it adheres to ethical and scientific standards aimed at protecting patients and affected populations from the risks involved in such interventions.

During the Ebola outbreak, the World Health Organization (WHO) developed a framework for the ethical use of unproven interventions outside research settings, involving collecting data on patient outcomes to contribute to the generation of new knowledge (WHO 2016). The framework was referred to as “monitored emergency use of unregistered and experimental interventions” (MEURI). It was later refined by the Pan American Health Organization (PAHO) to provide actionable ethical guidance for the COVID-19 pandemic (PAHO 2020a, 2022). To determine if it is ethically acceptable to offer unproven interventions outside research situations, PAHO organized the existing WHO criteria into four categories: the justification for the intervention, its ethical and regulatory oversight, an informed consent process and its contribution to the generation of evidence.

Yet the ethics framework for the emergency use of unproven interventions outside research was not widely known before the COVID-19 pandemic. At the inception of the pandemic, many RECs and relevant health authorities were not familiar with the criteria for determining whether it was ethical to offer unproven interventions outside research and what their role should be (e.g. whether RECs should review such proposals). This may partially explain why we have witnessed the use of several interventions, such as hydroxychloroquine, convalescent plasma, ivermectin, and even chlorine dioxide, outside research contexts without adherence to relevant ethics guidance (see Case 3.2 in Chap. 3). Case 6.5 illustrates the challenges faced by RECs when a proposal for use of an unproven intervention outside a research context is submitted for ethics review. It highlights the need for ethics guidance addressing this exceptional situation, which may arise during emergencies, including the appropriate roles of RECs.

6.4 Conclusions

A thorough assessment of the lessons learned during the COVID-19 pandemic can play an important role in strengthening ethics preparedness for future emergencies around the world. As illustrated in this chapter, ethics review challenges require more than implementing procedures to make ethics reviews faster and strategies to avoid the duplication of effort. The quality of the ethics analysis and the ability to adapt and respond to the emergency environment is also very important. The capacities of REC members may need to be strengthened so they are better prepared to conduct rigorous ethics reviews of emergency research in a timely manner.

The challenges that RECs have faced during the COVID-19 pandemic go beyond what these cases have illustrated. As discussed in other chapters in this casebook, additional issues raised in epidemics which need to be addressed to ensure that research is conducted ethically include devising feasible and meaningful community engagement strategies, mechanisms to ensure fairness in the distribution of the benefits that may result from research, and equitable and effective data-sharing plans that will inform pandemic response. Addressing these issues appropriately is essential for sustaining trust in research and, furthermore, in the interventions that result from research, which COVID-19 has revealed as crucial for ending the pandemic. Finally, we should critically evaluate which practices that were implemented in response to COVID-19 and have shown success (e.g. virtual meetings of RECs, electronic informed consent processes) and should be adopted into non-emergency ethics review and oversight processes. Lessons learned from this pandemic go beyond the ethics of emergency research and may help us to improve ethics review of research in the future.

Appendices

Case 6.1: Ethics Approval of a Multi-centre Study: To Expedite or Not?

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

Keywords

Ethics review; Research ethics committee remits and responsibilities; Risk/benefit analysis; Data protection, access and sharing; Safety and participant protection; Research priority setting; Multi-centre research; Treatment repurposing

While there were a number of licensed COVID-19 vaccines in use globally during 2021, the high cost and short supply meant that they were not expected to be readily available to the majority of the population in an Asian country until the end of 2021. Before that there remained an urgent need to find effective ways to continue treating patients.

In December 2020, the number of COVID-19 infections in the Asian country began to surge despite strict lockdown measures. Dr X. was a world-renowned medical researcher from an Asian country with extensive experience and knowledge of infectious diseases. She was appointed as a member of the COVID-19 task force in her institution and participated in a number of international COVID-19 initiatives. Some of the patients in Dr X.’s care developed cytokine storm syndrome, a common side-effect of severe COVID-19 and one which is potentially life-threatening. At the peak of the outbreak, Dr. X. and her team treated these patients with an IL-6 (interleukin 6) receptor blocker and saw tremendous improvements. Dr. X. began to design a randomized control trial to test whether this was an effective treatment for cytokine storm syndrome. The study participants would be divided into two groups, one receiving the IL-6 blocker and the control group receiving high doses of steroids as standard care. In order to increase the number of participants for better statistical analysis, Dr X. sought to expand her trial to include two other tertiary-level hospitals in the country which were COVID-19 centres.

Given the multi-site nature of the trial, Dr X. was required to seek ethical approval from each institution’s ethics review committee as well as from the national ethics review committee. Dr X. and her team were hoping that expedited pathways for COVID-19 trials would enable them to get approval within 2 weeks so that they could begin the clinical trial as soon as possible. Dr X. strongly believed that the findings would support her hypothesis that the IL-6 blocker would revolutionize the treatment of cytokine storm syndrome and save many lives. The ethics review committee at Dr X.’s institution provided ethical approval within 1 week. However, the two other ethics review committees only responded 3 weeks after submission and the national ethics review committee responded 4 weeks after submission. All three committees asked for more information regarding particular issues. Committee A was concerned about the risk of using steroids as a standard of care, noting that their institution might not be able to provide them because they were short of resources and personnel. Committee B raised a concern about the possible risks to patients and requested details about compensation to participants for adverse events. This committee was concerned that the families of the participants should be compensated for any medical complication due to the novelty of the disease, as well as research-related harms. Committee C highlighted data privacy issues resulting from collation of personal information about patients recruited from the three participating COVID-19 centres.

The feedback from the ethics review committees about these concerns was reflected in their requests for different amendments to the protocol. By the time these reviews came through, the peak of infections had passed and Dr. X. was seeing far fewer COVID-19 patients. Frustrated with the process, she decided to abandon the multi-centre trial and continue the treatment modalities as a clinical practice in her own institution.

Questions

• 1. Do you think that the requests from the ethics committees in this case were reasonable? Why?

• 2. What are the challenges of reviewing a multi-centre randomized control trial in a national health emergency?

• 3. During a global emergency, should there be a specific process to expedite ethics reviews of research proposals involving potential treatments? What timeframes would be reasonable? Which actors should be involved? Why?

• 4. In a national health emergency, are multiple ethics reviews of research studies a necessary step or is there another appropriate way of seeking ethical approval for multi-centre study? Why?

Case 6.2: Ethics Review of Multi-centre Trials: Challenges and Unforeseen Issues

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

Keywords

Ethics review; Research ethics committee remits and responsibilities; Safety and participant protection; Multi-centre research

With few treatment options available to manage COVID-19 during the early stages of the pandemic, the disease presented a unique set of challenges for health-care providers globally. Many prophylactic and therapeutic trials have been undertaken across the globe to generate evidence to inform the clinical care of patients with COVID-19.

The public health agency in an Asian country decided to investigate the effectiveness of using convalescent plasma to treat moderate COVID-19 in adults, using an open-label, parallel arm, Phase II, multi-centre, randomized controlled trial. About 50 public and private hospitals across the country expressed an interest in recruiting a total of 500 patients to the study between April and July 2020. Half the participants were randomly assigned to the intervention arm to receive convalescent plasma with standard care, and half received standard care only in the control arm. The objective of the trial was to assess the reduction in progress from mild to severe COVID-19 and the reduction in all-cause mortality. Participants in the intervention arm received two 200 ml doses of convalescent plasma, transfused 24 hours apart, in addition to standard care.

The study was coordinated centrally by a research and data coordinating centre and carried out at multiple hospital sites, using a common trial protocol. Conducting the trial presented various logistical and ethical challenges, including the following: planning the trial protocol, selecting participating sites, obtaining scientific/regulatory and ethics committee approval, conducting the trial across multiple sites, managing the challenges caused by lockdown, registering on the clinical trial registry platform, reporting serious adverse events from different sites, managing authorship issues for publication of the results, and converting evidence into practice.

All the sites willing to undertake the trial sought approval from their local ethics committee, as per standard requirements in the country. In view of the emergency situation posed by the pandemic, the trial was rapidly initiated and the recruitment commenced at all the centres as soon as the relevant ethics committee approval was received. In the country, only registered ethics committees can undertake ethics review of regulatory trials of this kind. An analysis of the status of ethics committees at these 50 sites showed that many of the trial sites did not have registered ethics committees, or had ethics committees with lapsed registration where renewal had not been applied for, or ethics committees that had applied for renewal and were awaiting their registration from the licensing authority. In addition, different ethics committees issued a range of recommended changes with respect to trial processes.

Questions

• 1. What logistical and ethical requirements should have been considered for the selection of the sites to participate in the trial? Should these include considerations relating to site preparedness, investigator qualifications and even local ethics committee capacity, training and/or registration? Why?

• 2. What should be done with the research data collected from the centres where the ethics committee registration status is invalid? Should administrative criteria like registration status be waived in an emergency like the COVID-19 pandemic? Why or why not?

• 3. For multi-centre clinical trials in a pandemic involving an intervention such as this, what role might a single (multi-site) ethics review play in ensuring the safety and well-being of participants? What should the division of responsibilities between local ethics committees and the multi-site common ethics committee be?

• 4. Within multi-site research in pandemics, what responsibilities are there to promote harmonized ethics review, effective monitoring, communication and networking between participating sites?

Case 6.3: The Importance of Effective Research Ethics Review

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

Keywords

Ethics review; Research ethics committee remits and responsibilities; Safety and participant protection; Research quality; Social and scientific value; Multi-centre research; Treatment repurposing

The COVID-19 pandemic brought countless challenges to research ethics committees, including how to deal with a challenging scenario that impacted risk–benefit analyses, and the need to conduct high-quality, rapid analyses of research submitted for ethics review.

A REC received a protocol for a randomized multi-centre clinical trial of a COVID-19 therapy for review. The protocol involved a trial of a therapeutic intervention that was being highlighted in the media and that was also highly politically contentious. In some places, with governmental financial support, the intervention was being provided as part of clinical care for patients diagnosed with COVID-19. The protocol did not contain details about the proposed randomization, nor did it explain what treatment would be used as an adjuvant. There were no references to published studies that would justify the proposal to conduct a Phase III clinical trial. Nevertheless, the project had already been approved by other RECs, despite these methodological flaws.

In addition to the proposal, REC members received information about the institution’s strong interest in the management of the research, and about media interest in the intervention. As a result, the REC members considered the possible repercussions of their decision. There were no members of the research team on the REC who could have acted as rapporteurs and provided more information about the study before excluding themselves from the REC’s deliberation and decision-making. While analysing the research, the REC identified additional questions relating to the participants’ safety, including a lack of procedures for participant monitoring. It also had concerns that the informed consent documentation was inadequate and did not cover relevant areas. Additional concerns arose about whether the study design could answer the research question and whether the principal investigator had an adequate team to carry out the study.

The REC members were divided about whether to approve the research or not. Arguments in favour of approving the research included that the REC should not intervene in the design of the research. Arguments against approving the research included there being insufficient information about the safety of the research and a lack of evidence about the research team’s capacity to ensure that risks and burdens of the research could be appropriately managed, and participants adequately protected.

In the context of the COVID-19 pandemic, the REC members felt they had heightened responsibilities, because of the increased vulnerability of the participants, the media attention and the institution’s interest and urgency with which it requested a response.

Questions

• 1. How should a REC manage potential conflicts of interest when there is a very strong institutional interest in undertaking a specific study to address an issue of high priority in a pandemic? Should the institutional interest have been disclosed to the REC? Why?

• 2. Does the fact that the intervention is already being provided to COVID-19 patients in health-care settings have implications for how a REC should review whether the risks of proposed research are justifiable? Why?

• 3. Should the REC evaluate methodological flaws in a protocol differently in a pandemic context where there is greater uncertainty and urgency? Why?

• 4. In a pandemic context where there is intense media interest in potential treatments, should REC evaluations of submitted protocols be influenced by the media? Why?

Case 6.4: Research into the Use of Ozone for Treatment of Patients with COVID-19

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

Keywords

Ethics review; Research quality; Safety and participant protection; Researcher roles and responsibilities; Treatment repurposing; Digital and remote healthcare and research

In the first months of 2020, several clinical teams tried different adjuvant therapies to treat patients with COVID-19. In one study in a country in Latin America and the Caribbean, researchers proposed to provide ozone by direct intravenous administration as a treatment for adult patients with COVID-19. All the procedures, including the preparation and administration of the ozone, would be carried out at the participant’s home by a registered nurse. The research protocol was over 150 pages long, with 10 pages assigned to the methodological design, and 23 annexes, including information about the researchers. Two of the three researchers were not registered as clinicians in the country where the study was being conducted.

The research protocol described different types of viruses and the use of ozone as a therapy for Ebola. The protocol noted that ozone had been used in isolated cases of Ebola, rather than being provided as an intervention in a study, and suggested that its use merited further investigation, given the reported recovery after an infection with such a lethal virus. This was the only information provided in the protocol about prior use of ozone as a therapy for a communicable disease in humans. One protocol annex referred to ozone as adjuvant therapy for COVID-19, indicating that the first records of its use should inform further research into its potential as an adjuvant to the treatment (Martínez-Sánchez et al. 2020; Ricevuti et al. 2020).

The inclusion criteria for the study were as follows: patients older than 21 years of age with suspected or confirmed infection with SARS-CoV-2, who did not have symptoms serious enough to require hospital treatment. The proposed research intervention consisted of a calibrated daily intravenous dose of ozone, combined with vitamin C tablets four times a day, for 3 days. According to the protocol, a nurse would carry out all the research processes from a vehicle outside the participant’s home. This would include the consent process, taking vital signs, blood samples, possible tests for COVID-19, and the administration of the ozone. The protocol did not adequately detail the biosecurity measures that would be undertaken to avoid infection. Participants would record all their symptoms and respond by telephone to a basic daily questionnaire about their behaviour.

The research ethics committee requested more evidence regarding the safety of the proposed intervention. They pointed to the importance of strict surveillance of ozone administration and additional clinical research into the risks associated with use of ozone therapy when co-morbidities might exist, including chronic diseases. After two rounds of ethics review and requested revisions, the committee continued to have concerns about ethical issues relating to confidentiality, the informed consent process, lack of good clinical practice training, and severe deficiencies in the protocol and its proposed methods. At this point the principal investigator sent a letter questioning the observations and the competence of the committee, as well as stating that the committee review was made “in bad faith”.

The committee sent one more letter to the principal investigator to enforce applicable regulations and cite the foundations for its outstanding questions. A few weeks later, the ethics committee accepted a request from the investigator to withdraw the study.

Questions

• 1. What effect, if any, should the lack of effective treatments in a pandemic context have on the ethics review of studies for a proposed treatment for COVID-19? Why?

• 2. In a pandemic context where infection-control measures are in place, should such a study be conducted in a person’s home and over the telephone? Why?

• 3. What qualifications should research teams have to conduct clinical research such as this? Should that vary based on where the study is being conducted and whether it addresses questions relevant to an outbreak or epidemic? Why?

• 4. Should the research ethics committee have rejected this proposal from the outset? Why?

References

• Martínez-Sánchez, G., A. Schwartz, and V.D. Donna. 2020. Potential cytoprotective activity of ozone therapy in SARS-CoV-2/COVID-19. Antioxidants 9(5): 389. https://doi.org/10.3390/antiox9050389.

• Ricevuti, G., M. Francini, and L. Valdenassi. 2020. Oxygen-ozone immunoceutical therapy in COVID-19 outbreak: Facts and figures. Ozone Therapy 5: 914–917.

Case 6.5: Reviewing the Use of Convalescent Plasma

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

Keywords

Ethics review; Research ethics committee remits and responsibilities; Research quality; Social and scientific value

At the beginning of the COVID-19 pandemic, to enhance research oversight response capabilities, the health authorities of a country in Latin America created an ad hoc national research ethics committee (NREC) responsible for reviewing all COVID-19 research to be conducted in the country.

During early stages of the pandemic, many studies around the world started testing convalescent blood plasma as a potential treatment for COVID-19 because there was evidence it had improved outcomes in patients with other diseases, such as Influenza A and Ebola, and because of its relatively low risk profile. In May 2020, the first protocol in the country aimed at determining the efficacy of convalescent plasma for COVID-19 was submitted to the NREC for review. In the following months five more protocols proposing to study the safety and efficacy of convalescent plasma for COVID-19 were submitted. All of them studied the same population (hospitalized moderate to severely ill patients); however, the study endpoints were diverse and the characteristics of the plasma used (e.g. its antibody level) were not standardized, which hindered comparison of findings across trials.

The first protocol, which was approved by the NREC, was a single-site, open-label, non-randomized trial with a sample of fewer than 100 participants. The second and the third studies, which were also approved by the committee, were multi-site randomized controlled clinical trials with samples of more than 200 participants. The remaining three studies were open-label and non-randomized clinical trials, and together sought to enrol approximately 200 participants. The members of the NREC deliberated about the seemingly lower scientific strength of these last three trials, the fact that they enrolled similar populations, and the implications of this for their review. Some NREC members argued that they should go on approving trials testing convalescent plasma in similar populations even if they were of lower scientific quality than the second and third clinical trials, which had already been approved. Ultimately, they decided that the urgency of advancing research to generate knowledge to address COVID-19 justified approving all the studies, even if they would produce weak evidence.

A few months later, the media reported that in high-income countries convalescent plasma was being provided to patients through expanded access or compassionate use programmes, on the basis of the modest evidence suggesting a positive benefit to risk ratio, given the lack of effective treatments for COVID-19 at the time. Taking note of this, people in the country started demanding that convalescent plasma be made available to COVID-19 patients outside the research context. Since the country did not have ethics or regulatory guidance for emergency use of unproven and unregistered interventions, convalescent plasma was given to some COVID-19 patients outside of a study protocol. In a few instances, clinicians requested that the NREC review these proposed therapeutic uses, and some members argued that the committee should provide oversight, because the use of unproven interventions outside of research should adhere to ethical standards. However, the NREC ultimately decided not to review emergency use applications, on the grounds that this fell outside its mandate.

Questions

• 1. In the pandemic context was it ethically justifiable for the NREC to approve all of the clinical trials testing convalescent plasma, considering their different scientific strengths? If so, why? If not, on what grounds should they have not approved certain studies?

• 2. Would it have been acceptable for the NREC to withdraw their approval of the first protocol, following approval of other protocols with stronger social and scientific value? Why?

• 3. Taking into account that all the trials were testing the same intervention in similar populations, what role, if any, should the NREC play fostering collaboration and coordination among the research teams to accelerate or enhance the research? Should the committee establish procedures to anticipate upcoming submissions, or is that beyond its mandate? Why?

• 4. Given the lack of ethics and regulatory guidance in the country regarding the emergency use of unproven interventions outside of research, should the NREC have reviewed the submitted request for therapeutic use outside a protocol? If so, are there any ethical issues that the NREC should consider in light of the potential for simultaneous use of unproven interventions outside of research and enrolment into clinical trials of those interventions?

Case 6.6: A Phase III COVID-19 Vaccine Trial

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

Keywords

Ethics review; Research ethics committee remits and responsibilities; Regulatory review; Vaccines; Emergency Use Authorisation; Multi-centre research; Placebo control

In January 2021, there was no effective anti-viral treatment for COVID-19. A mainstay of addressing both mortality and morbidity due to the disease is to vaccinate health-care workers, frontline workers and high-risk groups, including the elderly and those with co-morbidities. Initial vaccine development primarily occurred in high-income settings with relevant expertise and technology. By late 2020 many vaccines had begun receiving emergency use authorization (EUA) and several countries had begun rolling out vaccines for their populations. Some of the initial vaccines deployed after EUA included Vaxzevria, an adeno-virus vector vaccine developed by the University of Oxford and AstraZeneca, and the Pfizer Bio NTech and Moderna vaccines (both mRNA vaccines).

These vaccines were also sought by governments in low- and middle-income countries (LMICs) to use for their population, regardless of whether the vaccine was originally developed or tested in their country. Despite their approval elsewhere, in such circumstances, national regulatory agencies in LMICs often asked for a small bridging trial to ascertain safety and generate limited efficacy data to enable the regulator to grant an EUA. These studies were usually multi-centre, so as to be completed in the shortest possible time.

One vaccine manufacturer in a LMIC partnered with a vaccine manufacturer from a HIC to produce a vaccine which had received an EUA, using the same technology as the HIC manufacturer. A multi-centre placebo-controlled trial was planned with the approval of the drug regulator in October 2020 to ascertain safety and generate limited efficacy data before distributing the vaccine more widely. A key exclusion criterion in the trial was the presence of antibodies to SARS Co-V-2 indicating a past infection.

At their discussion of the ethical acceptability of the proposal, one of the members of a local research ethics committee argued that approval should be conditional on the national pharmaceutical company:

• (a) providing the vaccine free of cost to all those who were in the placebo arm

• (b) providing the vaccine free of cost to all the employees of the institution at the site where the study would be carried out, and

• (c) providing the vaccine at very low cost on a not-for-profit basis to the nation’s population once the EUA was received.

Questions

• 1. Is it ethically acceptable to conduct bridging trials of this type for vaccines that have already received an EUA elsewhere, if doing so will delay the introduction of the vaccine in a population? Why?

• 2. How do you think the researcher should respond to the ethics committee comments about the responsibility of the pharmaceutical company? Why?

• 3. If the trial did go ahead, what key topics which should have been addressed in the informed consent process?

Case 6.7: Research on Teleconsultation

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

Keywords

Regulatory review; Safety and participant protection; Research priority setting; Researcher roles and responsibilities; Digital and remote healthcare and research; Qualitative research; Researcher safety

During the COVID-19 pandemic, teleconsultations have become the preferred mode of delivery of health care, particularly when monitoring patients with chronic diseases such as diabetes, who require frequent check-ups and are at high risk of developing severe complications if they contract COVID-19. Patients can have teleconsultations with their health-care providers without having to visit the clinics or hospitals, thereby reducing their risk of exposure to infection. However, the effectiveness and safety of teleconsultations for monitoring patients with diabetes, who often also have other comorbidities, remain uncertain, especially in a country where teleconsultation is still relatively new.

In an Asian country, Professor A. and her team, who are responsible for diabetes care in their hospital, were keen to explore the challenges faced by doctors and patients when teleconsultations were used to monitor diabetes patients in a hospital diabetes clinic. They planned to interview both doctors and patients about the challenges posed by teleconsultations, as well as perusing the teleconsultation records to examine and understand the interactions. The team decided to seek the consent of the doctors and patients to take part in research interviews and share electronic medical records and teleconsultation records. The researchers planned to seek consent both verbally via telephone and electronically via e-consent, hoping that this would avoid the need for the participants to give their consent in person. The research project was approved by the hospital research ethics committee, which agreed with the research team that remote consent was appropriate in order to protect both patients and researchers from exposure to the SARS-CoV-2 virus at the hospital.

However, the research team faced an obstacle when applying to access the hospital’s electronic medical records, which were used for documenting patient teleconsultations. The country’s Telehealth Act, which was enacted 20 years ago but never formally enforced, does not permit clinical consultations to take place without a face-to-face consent process. The hospital’s legal adviser insisted that research participants needed to give written consent for researchers to access their electronic records during a face-to-face meeting. Despite being given an explanation of the potential benefits of teleconsultations during the pandemic, as well as the potential risks to patients and researchers of face-to-face consent, the hospital’s legal adviser insisted that the hospital would not take the risk of going against the law.

Consequently, Professor A. could obtain face-to-face written consent only from patients who came to the hospital for routine blood tests before their visits to the diabetes clinic. The progress of the research was slowed down significantly by slow recruitment as fewer patients attended the clinic since many of them were fearful about entering the hospital. Also, new Standard Operating Procedures during the pandemic meant that fewer appointments were scheduled each day. Professor A. and her team saw a reduction of about 70% in patients attending the clinic for regular blood tests. Professor A. also felt that it was unethical to expose the research assistants to the risk of catching COVID-19 when they sought to obtain consent from the patient in person.

Questions

• 1. What might be appropriate responses to institutional policies or legal regulations which appear to conflict with the changes in research practice proposed to enable research to be conducted ethically during a pandemic?

• 2. How should the hospital’s research ethics committee respond in a pandemic to the requirement to seek face-to-face consent, given the risks of infection to both patients and researchers?

• 3. What are the ethical implications of not conducting research into the safety and efficacy of rapid changes in clinical practice introduced in response to the pandemic (such as the use of teleconferences to aid patient monitoring)?