This article addresses an important, overlooked regulatory challenge during global health emergencies. It provides novel insights into how, and why, best practice can support decision makers in interpreting and implementing key guidance on conducting research during GHEs. The ability to conduct research before, during and after such events is crucial. The recent West-African Ebola outbreaks and the Zika virus have highlighted considerable room for improvement in meeting the imperative to research and rapidly develop effective therapies. A means of effectively capturing (...) these experiences and folding them into future decision-making is lacking; the need for effective practical translational measures remains. The challenge for the research community lies in extracting meaningful action-guiding content from pre-existing guidelines—which draw upon practical examples of guidelines ‘in action’—that assist in determining how to act in a particular situation. Insights are provided into the role of best practice as a means to do so; such examples can provide invaluable support to decision makers in interpreting high-level guidance; overarching guidelines retain their necessary level of generality and flexibility, whilst corresponding best practice examples—which incorporate important lessons learned—illustrate how such guidelines can be interpreted at a practical level. (shrink)

The unprecedented outbreak of Ebola virus disease in West Africa has raised several novel ethical issues for global outbreak preparedness. It has also illustrated that familiar ethical issues in infectious disease management endure despite considerable efforts to understand and mitigate such issues in the wake of past outbreaks. To improve future global outbreak preparedness and response, we must examine these shortcomings and reflect upon the current state of ethical preparedness. To this end, we focus our efforts in this article on (...) the examination of one substantial area: ethical guidance in pandemic plans. We argue that, due in part to their focus on considerations arising specifically in relation to pandemics of influenza origin, pandemic plans and their existing ethical guidance are ill-equipped to anticipate and facilitate the navigation of unique ethical challenges that may arise in other infectious disease pandemics. We proceed by outlining three reasons why this is so, and situate our analysis in the context of the EVD outbreak and the threat posed by drug-resistant tuberculosis: different infectious diseases have distinct characteristics that challenge anticipated or existing modes of pandemic prevention, preparedness, response, and recovery, clear, transparent, context-specific ethical reasoning and justification within current influenza pandemic plans are lacking, and current plans neglect the context of how other significant pandemics may manifest. We conclude the article with several options for reflecting upon and ultimately addressing ethical issues that may emerge with different infectious disease pandemics. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged conventional thinking about (...) therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

This paper examines the case of Ebola, ça Suffit trial which was conducted in Guinea during Ebola Virus Disease (EVD) outbreak in 2015. I demonstrate that various non-epistemic considerations may legitimately influence the criteria for evaluating the efficacy and effectiveness of a candidate vaccine. Such non-epistemic considerations, which are social, ethical, and pragmatic, can be better placed and addressed in scientific research by appealing to non-epistemic values. I consider two significant features any newly developed vaccine should possess; (1) the duration (...) of immunity the vaccine provides; and (2) safety with respect to the side effects of the vaccine. Then, I argue that social and ethical values are relevant and desirable in setting the parameters for evaluating these two features of vaccines. The parameters that are employed for setting up the criteria for assessing the features might have far-reaching implications on the well-being of society in general, and the health conditions of several thousand people in particular. The reason is that these features can play a decisive role during the evaluation of the efficacy and effectiveness of the vaccine. I conclude by showing why it is necessary to reject the concept of epistemic priority, at least when scientists engage in policy-oriented research. (shrink)

The recent Ebola virus disease outbreak in Western African countries has raised questions regarding the feasibility of adopting conventional trial designs such as randomized controlled trials for conducting experimental trials in the midst of a fatal epidemic. In the context of Ebola ça Suffit trial conducted in Guinea for testing the efficacy and effectiveness of rVSV–ZEBOV, a candidate vaccine, I argue that the trial design and the methodologies adopted for the trial have been rightly chosen for their ethical appropriateness and (...) social utilities rather than only epistemic advantages. In this paper, I propose and defend the view that in varying scientific research contexts, it is entirely legitimate that non-epistemic values may be prioritized over epistemic considerations. Two vital methodological choices scientists should make while designing a clinical trial are: the choice of appropriate control group and the choice of appropriate randomization. Given this background, I show that the choice of delayed vaccination arm as the control group over placebo control group and the choice of cluster randomization over individually controlled randomization for conducting Ebola ça Suffit trial are perfect instances of such a scenario where addressing social and ethical issues have been justifiably prioritized over epistemic values so that the research in a specific scientific context could be conducted in a socially relevant manner. (shrink)

The current Ebola virus epidemic in Western Africa appears to be spiraling out of control. The worst-case projections suggested that the unchecked spread could result in almost 1.4 million cases by the end of January 2015 with a case fatality rate of at least 50%. The United States and European nations have begun to respond in earnest with promises of supplies, isolation beds, and trained health care personnel in an effort to contain the epidemic and care for the sick. However, (...) there is neither a vaccine nor specific treatment for Ebola infection, and therapy is ideally centered on supportive care. I have previously argued that the provision of palliative care is obligatory during an overwhelming health catastrophe, notably pandemic influenza. Since affected Ebola patients have best outcomes with technologically advanced intensive care—resources in scarce supply in the area—I suggest that the only acceptable approach to large numbers of very sick, dying, and suffering Ebola patients who overwhelm the resources available to successfully manage them is effective palliative care. However, this could hasten death in this vulnerable population and hence, while ethically and medically justifiable, is not without social risk. (shrink)

The current Ebola virus epidemic in Western Africa appears to be spiraling out of control. The worst-case projections suggested that the unchecked spread could result in almost 1.4 million cases by the end of January 2015 with a case fatality rate of at least 50%. The United States and European nations have begun to respond in earnest with promises of supplies, isolation beds, and trained health care personnel in an effort to contain the epidemic and care for the sick. However, (...) there is neither a vaccine nor specific treatment for Ebola infection, and therapy is ideally centered on supportive care. I have previously argued that the provision of palliative care is obligatory during an overwhelming health catastrophe, notably pandemic influenza. Since affected Ebola patients have best outcomes with technologically advanced intensive care—resources in scarce supply in the area—I suggest that the only acceptable approach to large numbers of very sick, dying, and suffering Ebola patients who overwhelm the reso.. (shrink)

BackgroundThe global interest in developing therapies for Ebola infection management and its prevention is laudable. However the plan to conduct an emergency immunization program specifically for healthcare workers using experimental vaccines raises some ethical concerns. This paper shares perspectives on these concerns and suggests how some of them may best be addressed.DiscussionThe recruitment of healthcare workers for Ebola vaccine research has challenges. It could result in coercion of initially dissenting healthcare workers to assist in the management of EVD infected persons (...) due to mistaken beliefs that the vaccine offers protection. It could also affect equity and justice. For example, where people who are not skilled health care professionals but who provide care to patients infected with Ebola are not prioritized for vaccination. The possibility of study participants contracting Ebola infection despite the use of experimental vaccine, and the standard of care they would receive, needs to be addressed clearly, transparently and formalized as part of the ethics review process. Future access to study products in view of current status of the TRIPS agreement needs to be addressed. Finally, broad stakeholder engagement at local, regional and international levels needs to be promoted using available communication channels to engage local, regional and international support. These same concerns are applicable for current and future epidemics.SummarySuccessful Ebola vaccine development research requires concerted efforts at public dialogue to address misconceptions, equity and justice in participant selection, and honest discussions about risks, benefits and future access. Public dialogue about Ebola vaccine research plans is crucial and should be conducted by trusted locals and negotiated between communities, researchers and ethics committees in research study sites. (shrink)

The circumstances of a public health emergency shape reasoning and decision-making in ways that deviate from routine circumstances, where adherence to established values, principles, and methodologies is expected. Understanding what drives these deviations is critical to assessing their ethical consequences. In this paper we describe four conditions that influence decision-making during PHEs, in particular regarding the deployment and conduct of research on experimental or novel biomedical interventions. These four conditions are politicization, urgency, uncertainty, and fear. We argue that taken together (...) these four conditions create pressure to address the most visible targets of immediate crisis events, driving emphasis on research and development of biomedical interventions. However, this emphasis raises ethical concerns regarding the extent to which attention to and investment in the underlying causes of PHEs, particularly impoverished global public health infrastructure, is diminished as a result. (shrink)

As the usual regulatory framework did not fit well during the last Ebola outbreak, innovative thinking still needed. In the absence of an outbreak, randomised controlled trials of clinical efficacy in humans cannot be done, while during an outbreak such trials will continue to face significant practical, philosophical, and ethical challenges. This article argues that researchers should also test the safety and effectiveness of novel vaccines in wild apes by employing a pluralistic approach to evidence. There are three reasons to (...) test vaccines in wild populations of apes: i) protect apes; ii) reduce Ebola transmission from wild animals to humans; and iii) accelerate vaccine development and licensing for humans. Data obtained from studies of vaccines among wild apes and chimpanzees may even be considered sufficient for licensing new vaccines for humans. This strategy will serve to benefit both wild apes and humans. (shrink)

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical trials are conducted. Policy-makers are (...) swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs. (shrink)

The use of placebos in randomised controlled trials is a subject of considerable ethical debate. In this paper we present a set of considerations to evaluate the ethics of placebo controlled trials that includes: social value of the study; need for a randomised controlled trial and placebo; standards of care; risks of harm due to administration of placebo and the harm benefit balance; clinical equipoise; and double standards. We illustrate the application of these considerations using a case study of a (...) large ongoing multicentre, placebo-controlled, double-blinded, randomised trial to determine primaquine anti-relapse efficacy in vivax malaria. There is an urgent need for primaquine anti-relapse studies in order to rationalise the management of a potentially fatal disease. An ethical justification for the use of the placebo arm is provided on the grounds that the actual current applied standard of care in most endemic places does not include primaquine. It has also been argued that there is clinical equipoise among the primaquine study arms and that the risk of harms of being in the placebo arm is the risk of having relapse, which is no more than not being included in the trial, and that there are no double standards. Based on our set of considerations, we conclude that a placebo arm is not only justified but imperative in this study. We propose that similar considerations should be prospectively applied to other placebo controlled trials and observational control arms where no treatment is offered. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged conventional thinking about (...) therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

Ethics has been identified as a central reason for choosing the stepped wedge trial over other kinds of trial designs. The potential advantage of the stepped wedge design is that it provides all arms of the trial with the active intervention over the course of the study. Some groups receive it later than others, but the study intervention is not withheld from any group. This feature of the stepped wedge design seems particularly ethically advantageous in two instances: when the study (...) intervention appears especially likely to be effective and when the consequences of not receiving the intervention may be dire. But despite an increase in the use of the stepped wedge design and appeals to its ethical superiority as the motivation for its selection, there has been limited attention to the stepped wedge trial in the ethics literature. In the following, I examine whether there are persuasive ethical reasons to prefer or to require a stepped wedge trial. I argue that while the stepped wedge design is ethically permissible, it is not morally superior to other kinds of trials. To this end, I examine the ethical justification for providing, withholding, and delaying interventions in research. (shrink)