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The 2014 outbreak of Ebola viral disease in some West African countries, which later spread to the USA and Spain, has continued to be a subject of global public health debate. While there is no approved vaccine or drug for Ebola cure yet, moral questions of bioethical significance are emerging even as vaccine studies are at different clinical trial phases. This paper, through a normative and critical approach, focuses on the question of whether it is ethical to give any experimental drugs to Ebola victims in West Africa or not. Given the global panic and deadly contagious nature of Ebola, this paper argues on three major compassionate grounds that it is ethical to use experimental drugs on the dying African victims of Ebola.
Besides respecting patients and family consent in the intervention process, this paper argues that the use of Ebola trial drugs on West African population will be ethical if it promotes the common good, and does not violate the fundamental principles of transparency and integrity in human research ethics. Using Kantian ethical framework of universality as a basis for moral defense of allowing access to yet approved drugs. This paper provides argument to strengthen the compassionate ground provisional recommendation of the WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) on Ebola vaccines and vaccination.
Ebola virus disease (EVD), formerly known as Ebola haemorrhagic fever is a severe form of zoonoses with fatal illnesses in humans. The 2014 outbreak of Ebola viral disease in some West African countries such as Guinea, Liberia, Mali, Nigeria, Senegal, and Sierra Leone, spread beyond the African borders to Spain and the United States. During this period of its wide spread, the US National Institutes of Health and Centers for Disease Control and Prevention declared the Ebola as an epidemic out of control.1 While the Ebola epidemic was relatively out of control at some historical points till the early June 2016 that WHO declares an end to the outbreak, according to WHO data as of 30 July 2016, “an estimated 11,280 people have died during the current West African Ebola epidemic.”2 The Ebola virus is highly contagious and there are currently no licensed vaccines, drugs or treatment for it. Researchers are still developing drugs, vaccines to this effect. Such unlicensed drugs include ZMapp, developed and sponsored in the US by Mapp Biopharmaceutical, NanoSilver from Canada, Favipiravir an anti-influenza intervention, being developed by Fujifilm in Japan and Medivector, USA, TKM-Ebola, developed by Tekmira Pharmaceuticals, Canada, BCX4430, BioCryst Pharmaceuticals, USA, and vaccines such as NIAID/GSK Ebola by the US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline, UK, and VSV-EBOV, by NewLink Genetics, USA. In September 2015, an updated evaluation of these and other investigational drugs was conducted and reported by the WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) on Ebola vaccines and vaccination.3
Although an ethics panel of World Health Organization4 has given its recommendation on treating Ebola patients with experimental drugs, nonetheless, it is crucial to discuss in details the ethics of the use of such drugs in West Africa. This is exigent taking into account the vulnerability of the population in question and the non-completion of the approved stages of clinical trial phases that would establish the safety and efficacy of each of the ongoing interventions in humans.
Some fundamental ethical issues, therefore, arise from the proposal to ‘cocktail’ or not to use experimental drugs to contain Ebola in West Africa: who should weigh the risks and benefits of such drugs? Who should receive such drugs first: health workers or patients, and on what criteria? Who do we balance the issue of demand and supply in emergency triage? Who holds the financial responsibility for the payment of such unapproved drugs? Another moral question is how pharmaceutical companies will take care of liabilities in case the drugs have harmful side effects, especially in the developing world where health insurance is either non-existent or suboptimally operational. Related to this is the question of who gives consent for the use of experimental drugs and to what extent can such drug promote the common good?
This paper, through a normative and critical approach, however concentrates on the question of whether it was ethical granting Ebola patients access to unapproved and unproven drug interventions. One of the greatest concerns of allowing experimental drugs to be used on Ebola patients in West Africa is that in the eventuality of other future infectious outbreaks, there is the potentiality of slippery-sloping the clinical trial system in the region to an arbitrary level that may defy the logic of standard clinical research. This paper, therefore, argues that it is ethical to use experimental drugs on the basis of compassion and the common good. The paper asserts that the use of Ebola trial drugs on West African population will be ethical if it does not violate the fundamental principles of human good, transparency and integrity in human research ethics. Using Kantian ethical framework of universality as a basis for moral action, the paper establishes that giving trial vaccines on compassionate grounds in the face of Ebola outbreak can be universalized and this makes it ethical. It is only when such drugs are ‘cocktailed’ on an unprincipled ground that probing moral reasoning and questions against trail Ebola drug will justifiably suffice.
Ebola is a viral hemorrhagic fever disease often characterized by the sudden onset of fever, intense weakness, muscle, chest and abdominal pain, headache, lack of appetite, hiccups cough, and sore throat.5 There may be associated difficulty in breathing and swallowing. This is usually followed by vomiting, diarrhea, skin rash, red eyes, impaired kidney and liver function, and in some cases, both internal and external bleeding occur.6 Symptoms may appear between 2 to 21 days after exposure to Ebola virus. Some who fall sick are able to recover while others do not. The mode of transmission is believed to be from infected animals such as monkeys, gorillas and chimpanzees to humans. Health researchers also hold that Fruit bats are potential carriers of the lethal virus. It is also transmittable from human to human through body fluids- blood, urine, vomit, semen, faeces, saliva, touching of infected persons especially dead bodies.7
Ebola raises many concerns. The concerns of Ebola range from the obvious which is health to the cultural, political, economic, religious and ethical. The cultural aspect for example has to do with the way Africans care for the sick. In a highly communalistic society, it is expected that families and friends visit the sick as part of the care of the sick. Even burial rites include washing of the sick and cremation is alien to many African cultures. Should such cultural values be stopped, controlled or reduced to contain the contagious nature of the Ebola virus? Given that culture is about the people and their identity, should it be jettisoned for saving life? While this may not be easy to achieve in reality, on the religious scene, cremation and the burial rites of victims may call for a new way of burial activities. Even, certain practices such as the ‘holy handshakes’ among religious adherents may have to be regulated or stopped.
The health care systems of many African countries are fragile and weak; thus there are serious concerns in the management of such a deadly and highly infectious disease in Africa. Imposing experimental or militaristic policy on the people is not the way to go in effectively containing the Ebola epidemic. Education on how to be safe is important as that will in the long run form part of the people’s culture. However, this paper focuses mainly on the ethical dimension of EVD.
There are no known licensed drugs or vaccines for EVD yet. Although some interventions have been tested in animal models, but none is available for clinical use as the clinical trial phases have not been completed. The ethics of clinical research requires that before a drug can be used on human beings, appropriate clinical trials must have been conducted on it. The elements of clinical research process include: Pre-clinical testing, Investigational New Drug Application, Phase I trials that assess mainly safety; Phase II tests limited efficacy, while Phase III evaluates extended efficacy. After the three phases have been successfully conducted, then the drug goes for licensing. There could be exception to the standard rule in the case of licensed vaccines for use without passing through the three phases of trials. Outside this exception, approval is given making the drug or vaccine available for prescription and, lastly post-marketing studies which take care of special studies and long – term effectiveness or use of the drug. The ethics of clinical trials makes research scientific and provides information about the safety and efficacy of drugs or medicinal products. It therefore provides information for evidence- based medicine.
The dilemma is therefore that given that there are few drugs and vaccines, untested in humans for safety and efficacy, what do we do? There are some possible options. The first is not to cocktail any drug whatsoever until trials are completed. The second is to give anyway since it is an emergency situation and there is no alternative treatment. The third is to commence and fast-track the trial phases. One more option is to start using whatever is available and then start clinical trials later, or use what is on ground and concurrently start trials with them.
Does the clinical trial process and the scientific research protocol take into consideration or ever anticipate an epidemic such as the Ebola virus? Even with the rVSV-ZEBOV vaccine, an experimental Ebola vaccine, which has been recently announced as conferring total protection against infection in people who are at high risk of contracting the virus,8 the questions can be asked:9 Who do we balance the issue of demand and supply in emergency triage? What ethical reasoning and justification informed the Ebola trial drug use in West Africa? Are companies e.g., ZMapp under any obligation to produce more of these drugs even when not commercially viable? If they are and considering the cost of production of such drugs, who will pay for the risks in case the drugs have harmful effects? The equality that attends global health requires that all human beings be treated equally on health grounds hence application of such drugs must be universally applied. It is on this basis that Immanuel Kant’s10 ethical framework is adopted to establish the ethical justification of using experimental drugs in the containment of the EVD in West Africa.
Immanuel Kant argues that morality is concerned with the duty to obey unconditional moral laws. The commands of morality must be categorical imperatives, by which he means a moral law that must apply to all rational beings, regardless of their wants and feelings.11 His formulation of the categorical imperative is to establish that a morally good action is based duty and not on consequentialist considerations. Kant defines the categorical imperative as the following: “I ought never to act except in such a way that I could also will that my maxim should become a universal law.”12 while actions must be guided by reason alone to be in accordance with the moral law, maxims means principles guiding our actions. For Kant, a proposed maxim can fail to meet the above requirement in one of two ways. First, if the proposed maxim would become contradictorily impossible in a world in which it is universalized. Kant calls this type of contradiction a ‘contradiction in conception’ because it is impossible to conceive of the maxim being universalized.13 If an attempt to universalize a maxim results in a contradiction in conception, it violates what Kant calls a perfect duty.
Second, a maxim might fail by generating what Kant calls a ‘contradiction in willing’. This sort of contradiction comes about when the universalized maxim contradicts something that rational agents necessarily will. The second formulation of the Categorical imperative considers that the moral law is necessary and universal and that man has absolute worth. In this regard, Kant advocates that we treat humanity as an end and never as a means to an end. The imperative then states that “you use humanity, whether in your own person or in the person of any other, always at the same time as an end, never as a means.”14 These formulations will guide us through our ethical deliberations on the Ebola trial drugs.
Are we morally justified to cocktail experimental agents that have not been tested for safety in humans nor pass any clinical trial stage? Some arguments have been advanced against giving the experimental drugs and vaccines to victims of EVD. The ethics of clinical trials requires that before a drug can be used on human beings it must pass through the appropriate clinical trial phases. This will lead to a breach of scientific process which has in time past have caused a lot of horrors.15 Though the EVD situation is an epidemic requiring immediate intervention and outside the box thinking of research trial process, the moral concern is the potentiality of slippery-sloping the clinical trial system to an arbitrary level. Secondly, the data collected from such use may not be reliable for evidence- based medicine which emphasizes the use of evidence from well designed and conducted research in healthcare decision-making.16.
Anthony Fauci, a Director of America’s National institute of Allergy and Infectious Disease, advocates waiting till the completion of the trial phases.17 If the vaccine is shown to be safe for humans and effective, then the vaccine could be manufactured for human use for future use. In the face of the pandemic outbreak of EVD, taking side with Fauci’s option is the procedurally right thing to do but may not necessarily be the morally good option. The anxiety created by the absence of any intervention against the disease itself may affect mental health of the affected population. Considering the absolute worth of the human person in Kant’s second formulation of the categorical imperative and the potential offered by some of the experimental agents which could be used for treatment, it can be asked argued that the use of the trial drugs can be allowed when there is still the possibility that the therapy would be effective.
It may also be argued that testing the unregistered drugs on Africans, outside a clinical trial, may be seen as a discriminatory and an unfair deal. This is particularly so given the vulnerability of the population most involved in EVD. If the side effects of such drugs are harmful, then the mistrust of developing countries about developed countries may worsen, as they will be seen as unfairly experimenting on a vulnerable population. Further, the question of informed consent and autonomy comes to the open as there is mandatory treatment of victims in EVD epidemic. How do we handle inform consent and could there have been consent at all in the state of emergency as the outbreak of EVD presented? The principle of autonomy may be threatened as EVD patients may find it difficult to process information because of their state of health. They may be desperate to receive treatment or may even be scared of what the treatment entails.
The dreadfulness of the viral disease with its therapeutic uncertainties may impact on their inability to freely consent and decide on the treatment option(s). Considering also the fact that some of the affected patients may not be aware of clinical trials, research processes, drug experimentation, nor have informed awareness about advance directives, they may not be able to adequately consent to the cocktailing of investigational agents on them. Infrastructural facilities needed in healthcare centers for standard care of Ebola patients are quite weak in many African states, especially in the face of the current outbreak. Given all these points, it is perhaps suggestive that the investigational agents should not be used. While these and other related ethical concerns in the study design of therapeutics for EVD epidemic have been engaged and guidelines drawn by the WHO Ethics Working Group,18 it is important to relate how Kant’s theory support or refute such guidelines.
One of the guidelines provided by the WHO Ethics Working Group states that “consent processes must be adapted to contextual limitations. Innovative approaches may need to be considered to ensure comprehension and voluntariness. These could include video or audio recordings or, in some cases, surrogate consent.”19 A Kantian appraisal of this guideline shows that it is in dissonance with the formula of universal law – “act only on that maxim through which you can at the same time will that it should become a universal law.” The question can be asked: should consents be adapted to local context, or should contextual limitations define what constitute consent? Adaptation implies flexibility; flexibility in ethical standards is susceptible to double standard and whims and caprices of whoever is in position of authority. Irrespective of how the questions are viewed, the universal characteristic of informed consent and its ethical necessity in clinical research trials is compromised. The environment of EVD is also something that calls for concern. Given that most patients are quarantined, the stigmatization usually associated to such is enough not to be in a good state of mind for decision making. Quarantine and other public health measures violate the right to freedom of movement, just as aspects of contact tracing and the notification of third parties can interfere with the right to privacy.20 To the extent that public health maintenance requires that such measures be taken, the critical question remains should the goal of protecting the greater societal good take priority over promoting individual rights and freedoms? Because of the difficulties involved in balancing the divides, perhaps it is suggestive that trial drugs and investigative agents should not be considered during the EVD epidemic.
It is publicly given that in the context of the Ebola epidemic in West Africa, WHO maintained that “it is ethical to make investigational therapeutics available outside of clinical trials for “emergency use” provided clinical data from their use is systematically collected and shared.” Without necessarily controverting this position, this paper considers important providing some further arguments to strengthen the position of giving intervention agents to Ebola victims. The contention of this paper is that the use of experimental or untested drugs in the outbreak of EVD can be morally allowed on ‘monitored-compassionate’, common good and self-prudential grounds. Though un-Kantian like, the self-prudential ground for giving intervention agents is instructive. Not providing accessibility to intervention agents would have made the West African EVD population more vulnerable. Such vulnerability is most expressed given that EVD has “mostly affected economically deprived countries as limited resources adversely affect a country’s infrastructure and public health administration.”21 Many of the West African states affected by EVD have “irresolute and disorganized health systems, substandard sanitary conditions, poor personal hygiene practices, and false beliefs and stigma related to EVD.”22
There tends to be a vicious cycle existing between the Ebola epidemic in West Africa and poverty. Not only that the foregoing variables make the people more vulnerable to EVD, but also that EVD, in turn, promotes poverty as the economies of the states also suffered just as the victims and their families are disempowered. Arguably, many of the conditions that affected and promoted the EVD epidemic are rooted in historical injustices, of both internal and external dimensions. If global justice requires poverty reduction and the provision of the means of reducing poverty and disease in developing world, then justice requires the containment of EVD through provision of drug interventions in the West African region. Indeed, making such agents available would be more self-prudential given the mobility of EVD. The EVD epidemic in developing countries of West Africa is most likely to have negative implications for public health in rich countries. Thus, it is self-prudential that to protect their own populations, rich countries have a duty to take greater interests in making more of the experimental drugs available to EVD victims in West Africa and support improved healthcare system.
One justification given for cock-tailing experimental agents on EVD victims, according to the WHO Ebola Ethics Working Group, is what has been termed “monitored emergency use of unregistered and experimental interventions (MEURI).” This phrasing should not be confused with ‘compassionate use’, which can also involve “an investigational intervention for patients outside of an ongoing clinical trial or the indicated scope of utilization.”23
The compassionate or expanded use program allows medicinal products that have not passed through clinical trials to be made available to patients with severe diseases who have no other treatments available to them. For example, the European Regulation 726/2004/EC legislates for ‘compassionate use’ programs in the European Union.24 It allows groups of patients with a chronic, seriously debilitating, or life-threatening disease, without a satisfactory authorized treatment available, and who cannot take part in a clinical trial, access to an unlicensed medicinal product. Such drugs must be the subject of a market authorization application, or under evaluation in a clinical trial. The patient, however, is the central focus and such uses are without control groups.25 The US Food and Drug Administration (FDA), which regulates drugs administration and evaluates clinical trials sponsored by US agencies, also allows the use of untested drugs on compassionate ground. While there is the absence of such reputation in the context of African Union, the pertinent question to raise concerns how compassionate is ‘compassionate use’ of unregistered interventions in Africa?
Unlike the phrase ‘MEURI’ used by the WHO Ebola Ethics working Group, Whitfield et al26 prefers to use the word “expanded access” since the word compassion describes the wish to relieve suffering while the benefits and harms are not known. However, using ‘expanded access’ clues directly on an extension of the use of such drug, which is granted while the information on the benefits and harm is not yet available. Irrespective of the choice of terms, ‘monitored-compassionate’ use of an intervention agent is not simply about following scientific procedures but doing the good that will help victims stay alive in emergency and epidemic situation. Monitored compassionate use has the goal of saving human life, reducing the suffering of the patients and promoting human dignity in health care systems. To deny access on such ground would amount to a grave injustice. Although it can be argued that for any drug to qualify for compassionate use, it must at least pass through phase I of clinical trials.27 At this point we cannot gloss over the risks of ‘monitored-compassionate’ use programs. Clinical trials are expected to be conducted systematically in different populations so as to give information on the safety of such drugs. Thus, compassionate use cannot be replaced with randomized clinical trials. Given the high contagious nature and life-span digression spate of EVD without any registered drugs or vaccine, we can extend monitored-compassionate use or expanded access to intervention agents. Apart from the fact that using intervention agent satisfies the beneficence as a major principle of a research process, it can be argued that intervening in EVD cannot simply be left to the research process. This is so because as an epidemic, there is a moral duty on the researcher to provide care to an infected subject. This would not be considered, simply, as doing good for the individual subject of patient; it would also be seen as contributing to a common good through helping to curb the worsening of an epidemic.
Arthur L. Caplan is correct in arguing his argument in support of compassion as a moral ideal in a time of Ebola.28 According to him, the goal of compassionate use of intervention agents “is to help those patients in desperate need rather than to simply do research on them.” He writes on the ethics of compassionate use in a context of epidemic like Ebola:
… the moral response to panic or desperation is not simply to throw all available resources at any imaginable idea or experiment. Attention to justice, effectiveness, and science are required, even in the face of a fast-moving, incurable infectious disease. Justice during a crisis requires that the bulk of available aid and resources go to the provision of proven interventions rather than new possibilities. Resources ought to go to the measures that promise the best chance for effectively ending the spread of the epidemic and treating the sick rather than to long-shot attempts at rescue.29
The above possible ethical justification of monitored-compassionate use notwithstanding, when such agents are used, they should have at least a minimum regulatory procedure, be regulated and monitored for responsible use. But the fundamental question is what the role of WHO consists in ensuring responsible use and allocation of intervention agents?
The particular circumstances and the global threat of the current EVD outbreak have continued to gain attention of international agencies, the WHO in particular. WHO intervened on the 11th of August, 2014 and the summary of their meeting was that in the particular circumstances of this outbreak, and provided certain conditions are met, it is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects, as potential treatment or prevention.30 Ethical criteria must however guide the provision of such interventions. These include transparency about all aspects of care, informed consent, freedom of choice, confidentiality, respect for the person, preservation of dignity and involvement of the community.
In order to understand the safety and efficacy of these interventions, the group advised that, if and when they are used to treat patients, there is a moral obligation to collect and share all data generated, including from treatments provided for ‘compassionate use’. Other issues that border on the ethics of these drugs include: ethical ways to gather data while striving to provide optimal care under the prevailing circumstances; ethical criteria to prioritize the use of unregistered experimental therapies and vaccines; ethical criteria for achieving fair distribution in communities and among countries, in the face of a growing number of possible new interventions, none of which is likely to meet demand in the short term.
The WHO’s intervention and discussion was timely and well taken. However, “the WHO managed to convene the said meeting without a single representative from any of the countries affected directly by Ebola.”31 It is important that countries directly concerned be adequately represented so that they can formulate regulatory policies and be responsible for such policies.
The regulatory roles of the Nigerian National Health Research Ethics Committee (NHREC) cannot be underestimated in the effective containment of EVD. Prior to the WHO’s declaration of Nigeria as Ebola free-state, the Committee considered agents such as ZMapp and other agents for treating Ebola as innovative or non-validated treatments.32 According to its biomedical ethical code of conduct, such treatments are designed solely for the benefit of the patient. However, the ability of the treatment to provide the desired result is to some degree not proven. Such drugs are therefore granted exemption though on the recommendation that they should be subjected to research in order to generate information about their efficacy as soon as possible. In its advisory capacity, the Committee advised the government that researchers may not need to submit an application to National, State or Institutional Health Research Ethics Committee for prior review and approval. There is a strong call for proper documentation of the efficacy and protocols of such trials.33.
In a further attempt to promote rapid international response to the global emergency to EVD, the committee also waived the current requirement that international shipment of any biological samples out of Nigeria should be preceded by the establishment of a Materials Transfer Agreement (MTA). The spirit of this declaration was understood the emergency situation required emergency, quick response and intervention. This consideration appears too large, too generous and too risky. While the IRB, NHERC may be advised to fast-track their deliberations, the current positions of the NHREC may create room for abuse and unnecessary loopholes.
The principle of research ethics advocates that, in any given research, there must be strict informed consent. Information must be adequately given to patients on the nature of the drug or vaccine. The options must be clearly presented and for those who cannot give consent the parents, guardians or relatives should be able to stand in for the patient(s). This should not be jettisoned even in the face of an emergency. The export country concerned should also consent to the use of the drug in the receiving state. This is one of the regulatory measures that call for a sense of responsibility on the government of each concerned states.
It is important to address the question of who should have access to this compassionate use of drugs. The American example has shown clearly the argument that medical professionals should have access first.
It can be argued that they are the “first-spreaders”, “super-spreaders”, most vulnerable and they are at high risk of infection because they have more physical contacts with patients. When viewed from the context of clinical trials, medical professionals ought to understand what clinical trials entail and expectedly, having their informed consent may raise fewer concerns. Given that the principle behind compassionate use primarily is about the patients, it then becomes ethical to allow patients to access any available drugs first. However, in a case that the medical personnel are patients and ‘first-spreaders’, the qualification for access becomes higher and thus ethical.
Compassionate use of drugs presents the issue of placebo and control group. According to Joanna Monti-Masel,34 the ethical thing for the USA to do would have been to give one of the available doses to one of the doctors by tossing a coin and the other to an African patient while other preselected American and Africans should get a placebo. She advocates randomized double blind placebo trials even with the few drugs available as this would have helped to determine the efficacy of the drug on an even population.
This paper aligns with the suggestion of researchers that calls for a “step-wedge” trial.35 This type of trial analyses what happens to people at similar risk who receive the vaccine at different times. This will enable those who have been vaccinated to be compared with others who have not yet received theirs. This is feasible as all of them cannot receive their shots at the same time in a day.36 This method also has its own limitation. The rate of spread and level of immunity can differ and personal protective measures can also differ.
It is also possible to suggest “small scale-trials” on all experimental drugs and vaccines with a data coordinated approach under a body such as WHO. This may not be comparable with standard procedures but at least will help to decide on potential treatments so that effective ones can be encouraged and ineffective ones dropped along the line.
Ebola is a concern to all. We live in a global, international, interconnected village. EVD is a communicable disease and it does not respect borders. This makes us all to be potentially vulnerable. More developed and developing countries should all be bothered as EVD is a global concern. As medical researches on EVD progress, supportive care should be optionally given to patients. As a public health issue, preventive health measures should be improved and awareness created about the disease. Africans need to be pro-active and more health conscious just as the failing states in Africa should see as urgent, overhauling of their existing health care systems. More health equipment should be deployed to hospitals and schools and adequate safety measures given to health workers.
The Bioethics Online Journal (BeOnline®) is supported by Award Number R25TW007091 from the Fogarty International Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Fogarty International Center or the National Institutes of Health.
NB: The first version of this paper titled “The Ethics of Ebola Drug Trials: to give or not to give” was presented at the Bioethics Seminar meeting which was held on Thursday, 25th September 2014 at the Seminar room, Department of Surgery, University College Hospital, Ibadan, under the auspices of West African Bioethics (WAB) Training Programme.