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13. The Use and Study of Unregistered Ebola Interventions: Ethics and Equipoise

Published onMar 28, 2020
13. The Use and Study of Unregistered Ebola Interventions: Ethics and Equipoise
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Use of Unregistered Interventions

The World Health Organization (WHO) declared the Ebola virus disease (EVD) outbreak in West Africa a public health emergency of international concern on August 8, 2014. At the time, 1,711 cases of EVD, and 932 deaths, had been reported.1

The following week, on August 11, 2014, WHO convened an advisory ethics panel “to consider and assess the ethical implications for clinical decision-making [regarding the] use of unregistered interventions [for EVD] that have shown promising results in the laboratory and in animal models but that have not yet been evaluated for safety and efficacy in humans.”2 This meeting was (presumably) largely motivated by high-profile (media) controversy surrounding treatment of health care workers from wealthy developed nations (that became infected with Ebola in West Africa) with the monoclonal antibody ZMapp upon return to their home countries. The use of ZMapp in such patients was controversial partly because it raised questions about why (only) health workers from wealthy developed countries were being treated with this intervention (in very short supply) rather than patients in West Africa. The use of ZMapp was also controversial because this intervention had never previously been tested or used in humans, whereas standard medical practice is that the earliest human use of an intervention generally occurs in Phase 1 clinical trials—for evaluation of safety—prior to actual use in patients.

The WHO panel was thus posed with the question whether it is ethically acceptable to use unregistered medications that have never previously been tested in humans in the context of the emergency Ebola crisis unfolding in West Africa. In addition to ZMapp, this question was relevant to numerous other candidate drugs and vaccines there was reason to believe might be promising interventions against Ebola, though they had likewise never been previously tested in humans. Some of these other interventions, like ZMapp, had shown especially promising results in animal studies.

In response to this question, the panel members unanimously concluded that it may be ethically acceptable to use unregistered medications (not previously tested in humans) in the context of the emergency EVD situation, so long as various basic ethical conditions are met:

The ethical criteria include transparency about all aspects of care, so that maximum information is obtained about the effects of the interventions, fair distribution in the face of scarcity, promotion of cosmopolitan solidarity, informed consent, freedom of choice, confidentiality, respect for the person, preservation of dignity and involvement of the community. Use of these interventions should also be based on the best possible assessment of risk and benefit from the available information.3

The panel furthermore concluded that when interventions are used in such contexts, it is important that we learn as much as possible about the safety and efficacy of the interventions in question:

if and when these interventions are used to treat patients (or as prevention), the physicians overseeing their administration have a moral obligation to collect and share all scientifically relevant data generated, including from treatment provided for “compassionate use” (access to an unapproved drug outside a clinical trial), in order to establish the safety and efficacy of the interventions.

The group discussed how use of these investigational interventions in a clinical context can be evaluated scientifically to ensure timely, accurate information about their safety and efficacy. They agreed unanimously that investigators have a moral duty to evaluate these interventions (for treatment or prevention) in the best possible clinical studies that can be conducted under the circumstances of the epidemic in order to establish their safety and efficacy or to provide evidence to stop their use. Continuous evaluation should guide future interventions.4

This insistence on scientific evaluation of the use of unregistered interventions is at least partly justifiable on justice grounds. The fact that there were not already registered interventions against Ebola, that is, arguably reflected prior wrongs. Given familiarity with Ebola for almost forty years before the West African outbreak, one might have expected that there should already have been more testing and development of interventions against the disease—and that we should not, in 2014, have been in a situation where it was necessary to resort to the use of unregistered medications that had not yet even gone through Phase 1 trials in the first place. Why were there not already registered interventions against Ebola, and why were we not already further down the research and development pipeline for Ebola vaccines and therapeutics? One reason more Ebola countermeasure research and development had not already previously taken place is presumably that we rely so heavily upon private enterprise—that is, pharmaceutical companies with profit-driven, self-interested motives—to determine what research does and does not get done. The previous 40 years of experience with Ebola was limited to small outbreaks in rural villages in poor African countries. Given that it had previously only affected small numbers of people in poor countries, Ebola was not the kind of disease that would appear to provide good return on investment—and so the lack of more Ebola countermeasure research and development is ultimately unsurprising. One lesson learned from the Ebola epidemic is arguably that it is a mistake to rely so heavily on private enterprise to develop and provide solutions to what are ultimately public problems.

Equipoise and Prioritization of Use and Study of Unregistered Interventions

The WHO panel’s insistence on scientific evaluation of the use of unregistered interventions, in any case, raised further questions about the ethics of scientifically studying the use of such interventions in the emergency context of Ebola. Regarding the question of who should be prioritized to receive experimental interventions in limited supply or where relevant studies should take place, the WHO Ebola Ethics Working Group (tasked with addressing this and related questions) ultimately concluded:

The recipients of experimental interventions, locations of studies, and study design should be based on the aim to learn as much as possible, as quickly as possible, without compromising patient care, local community values or health worker safety. Trials should be designed and conducted with the active participation of local scientists and researchers, and with proper consultation with communities and local ethics committees.5

It is noteworthy that this answer differs from those commonly given to questions about who should be prioritized to receive limited supplies of drugs, vaccines, and so on in other contexts. In the context of pandemic influenza, for example, it has commonly been argued that health care workers and children should be prioritized to receive interventions in limited supply in order to promote both utility and fairness.6 A utilitarian reason to prioritize health workers is that health workers are needed to fight pandemics—so keeping health workers healthy and alive has especially important societal benefits. A fairness-based reason appeals to the principle of reciprocity: Health workers provide a valuable service to humanity by facing risks associated with health care provision, so society owes them something back in return. A utilitarian reason for prioritizing children over older persons is that, other things being equal, more lost years of life can be averted by saving the life of a younger rather than an older person. A fairness-based argument for prioritizing children appeals to the “fair innings” argument—the idea being that it would be unfair if a child is killed prematurely and thus does not have the opportunity to live through all the stages of life (which, according to some, one has a right to do).

Both kinds of rationales in both kinds of cases, however, depend on the presumption that we are talking about prioritization of interventions that are safe and effective, and ultimately expected to be beneficial. This, however, cannot be taken for granted in the context of unregistered, experimental interventions that have not previously been tested in humans. Whether or not such rationales for resolving questions regarding resource allocation in pandemics should also apply to questions surrounding prioritization of unregistered experimental Ebola interventions depends on whether there is reason to be confident that recipients of such interventions are more likely than not to benefit from the interventions in question. Even in cases where there have been especially promising (safety and efficacy) results in animal testing of an intervention, this may not provide grounds for confidence that the intervention in question would be beneficial to humans—because it is notoriously difficult to translate animal findings to humans. Whether there were good grounds for confidence that particular candidate Ebola interventions would have been more likely than not to benefit human recipients is ultimately a scientific question beyond the scope of this chapter. The main point for now, in any case, is that answers to ethical questions about prioritization of unregistered Ebola interventions ultimately depend on answers to this kind of scientific question (which has not, to my knowledge,7 been answered).

While the above rationales for prioritization of limited interventions (proven to be safe and effective) in pandemics may not help answer questions about who should be prioritized to receive experimental interventions for which we are in a state of equipoise—that is, where there is no reason to be confident that the intervention is likely to be more beneficial than available alternatives, or vice versa—there may still be good reasons to prioritize health workers in the latter kind of case. In light of the WHO Ebola Ethics Working Group’s statement that prioritization decisions should, inter alia, “be based on the aim to learn as much as possible, as quickly as possible,” a reason to prioritize health workers, at least in the case of vaccine trials, is that (other things being equal) it is possible to learn more about the efficacy of a vaccine by using it in those most likely to be exposed to the pathogen in question; and health care workers treating Ebola patients are especially likely to be exposed to the Ebola virus. Another good reason for prioritizing health care workers is that they are more likely to be able to give proper informed consent, especially in the West African countries most heavily impacted by Ebola—because health workers are among the most literate citizens of these countries (and because they have specialized knowledge especially apt for informed consent to medical intervention).

Equipoise and Placebo-Controlled Trials

The question of equipoise is likewise relevant to questions surrounding the ethical design of scientific studies of unregistered Ebola interventions. While some have voiced opposition to placebo-controlled trials of Ebola therapeutics because this would deprive some patient-participants (i.e., those who end up receiving placebo) with a highly fatal disease from potentially efficacious therapy8—the idea that it would be unfortunate to receive placebo rather than the intervention being tested depends on the presumption that there is reason to be confident the intervention being tested is actually more beneficial than placebo. If (despite promising results in animals) we really are in a state of equipoise, then there is no reason to believe it would be worse to receive placebo than the intervention under investigation. In addition to uncertainty about efficacy, uncertainty about safety of unregistered experimental interventions would remain even after Phase 1 trials are conducted—so receipt of an experimental intervention could do more harm than good (i.e., it might ultimately be preferable to receive placebo rather than the experimental intervention). Those who receive placebo in such a trial, in any case, would not be deprived of anything available to those who do not, or are unable, to participate in trials to begin with (which would inevitably be the case for many Ebola patients given limited supply of numerous candidate experimental Ebola interventions)—so (other things being equal) no harm would result from participation in a placebo-controlled trial. If it is assumed for the sake of argument that the intervention under investigation is likely to be more beneficial than placebo, on the other hand, then one would arguably benefit from participation in a placebo-controlled trial—because one could thus gain the opportunity (not available to nonparticipants) to receive the intervention.9 One of the main objections to placebo-controlled trials of Ebola therapeutics (i.e., that such trials would deprive participants of access to potentially beneficial interventions) is thus arguably unpersuasive whether or not there is a state of equipoise.

A better reason for being ethically opposed to conducting placebo-controlled trials of Ebola interventions in the most heavily affected countries, on the other hand, is that representatives of these countries repeatedly made clear at WHO meetings that local communities would consider such trials to be unacceptable (precisely because of perception that such trials would deprive some participants of access to potentially beneficial interventions). Whether or not more or better community engagement (e.g., explaining the usual rational for placebo-controlled trials and why there might not be any good reason to assume that those who receive placebo would be disadvantaged if there really is a state of equipoise) would have changed local community attitudes toward, or resulted in acceptance of, placebo-controlled trials is perhaps an open question. Effective community engagement regarding such matters in the context of the Ebola crisis in West Africa, however, might not have been very easy given the actual situation on the ground.10 Whether or not local community rejection of placebo-controlled trials is ultimately rational or well-informed, local community acceptance is arguably a necessary condition of the ethical acceptability of research involving human subjects.11

Acknowledgment

Though I was a member of the WHO ethics panel and WHO working group discussed in this chapter, opinions expressed here are my own rather than (except where explicitly stated) those of WHO.

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Copyright © 2016 Massachusetts Institute of Technology. (All rights reserved.)
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