Epidemics and pandemics of novel pathogens are often characterized by a lack of known therapeutic or preventive interventions; COVID-19 is of no exception. It is therefore imperative to rapidly conduct research to study and develop countermeasures in these contexts. Yet, with research underway and no 'proven' therapeutic or preventive interventions, clinicians and healthcare systems have to assess whether individuals, groups, or populations should be offered 'unproven' preventive and therapeutic interventions outside of clinical trials, including “off-label” interventions. This seminar explored the use of 'unproven' clinical interventions during public health emergencies, coinciding with the recent publication of the World Health Organization's guidance document, "Emergency use of unproven clinical interventions outside clinical trials: ethical considerations".
• Prof. Ross Upshur, Head, Division of Clinical Public Health, Dalla Lana School of Public Health, University of Toronto, Canada.
• Dr Alison Bateman-House, Assistant Professor, Division of Medical Ethics Department of Population Health, NYU Grossman School of Medicine, New York, USA.
• Dr Ignacio Mastroleo, National Scientific Council (CONICET) & Program of Bioethics of the Latin American Faculty of Social Sciences (FLACSO), Buenos Aires, Argentina.
• Dr Marta Lado Castro-Rial, Case Management Expert, WRE, World Health Organization, Switzerland.
Dr Bateman-House began her presentation by arguing that during a public health emergency, normative claims about clinical interventions are meaningless without structural supports which allow for their effective implementation. Capacity is therefore a prerequisite to treatment, without which clinical interventions will not be effective. In regards to ‘unproven’ interventions, Dr Bateman-House argued that clinicians, researchers and public health officials working for the executive arms of national governments, have a collective obligation to proactively identify and authorize individuals and entities who are responsible for the rapid generation of high quality data, and the translation of that data into evidence that can be used to practical effect. She also stated that clinicians need to differentiate the duty to treat with the duty to research. In this case, the duty to treat – in other words intervene – is provisional; it extends only to proven interventions (and even these may be withheld in certain circumstances; for example in the event of scarcity, or because treatment places clinical personnel at risk.) The duty to research involves the ability to quickly develop evidence-based practises for both the good of individual patients and the population, and may outweigh individuals’ desire to try unproven products outside of clinical trials and clinicians’ normal prerogative to treat patients as they deem best. [12.10] Nevertheless, there must be structures in place to prioritise the most important research and disseminate findings. Dr Bateman-House concluded that in exceptional circumstances in which proven options are unavailable and participation in a clinical trial is not possible, unproven interventions can be provided to patients outside of trials. A clinician may opt to use an unproven intervention for the patient’s therapeutic benefit, but there is no moral obligation to do so. Furthermore, any action must comply with relevant laws, including informed consent, and it must be possible to collect at least safety data. Once sufficient evidence emerges that a given intervention is helpful, governments can develop policies to facilitate wider access for the benefit of society.
Dr Ignacio Mastroleo followed-up on Dr Bateman-House’s comments, stating that the World Health Organisation’s MEURI (monitored emergency use of unregistered and experimental interventions) protocol was created in 2014 in response to the West Africa Ebola outbreak. This was done, both to avoid using the misleading term of ‘compassionate use’ but also in order to develop a robust ethical framework for such interventions. In regard to the question is it ethically permissible to use unproven interventions outside of clinical trials during a public health emergency, Dr Mastroleo argued in principle it is. However, paradoxically it is also ethically mandatory to restrict and forbid certain unproven interventions outside of clinical trials during a public health emergency if, for instance, they are likely to cause harm. Clinicians must balance individual health, autonomy and beneficence in the context of an existential threat to humanity or large populations that can be effectively prevented or managed only by collective action (WHO, 2022:4-5). Regulatory bodies and research ethics committees charged with evaluating the use of unproven interventions outside of clinical trials in public health emergencies, must contend with the fact that the MEURI ethical framework is not well known, and is inherently complex. For example, monitored emergency use interventions are a non-research-based activity; however the main aim is research-based in that it aims to benefit patients, groups and populations through the accumulation of evidence. Like research it has more stringent ethical requirements, and finally it has a complex correlation to governance structures and regulations, or a lack thereof. If unproven interventions are used outside of clinical trials they should be evaluated in relation to the MEURI ethical framework, and in particularly the four ethical categories of justification, ethical and regulatory oversight, consent process and contribution to evidence. It can then be implemented in relation to the recommendations as set out in the guidance.
Dr Marta Lado Castro-Rial [26.15 – 36.50] drew directly from her experience working as clinician managing multiple Ebola Outbreaks in West Africa; particularly the Democratic Republic of the Congo. She noted that with Ebola, the prognosis is bleak. Therapeutics aren’t available, treatment is often palliative and the mortality is high. In this context, the question of whether it is permissible to use unproven interventions outside of clinical trials during a public health emergency becomes urgent. In the DRC, Dr Castro-Rial utilised the MEURI framework as a way to permit unproven interventions, which could also be justified under the ethical guidance, by the following preconditions: firstly, the absence of clinical trials, secondly, the evidential support for safety and efficacy obtained from laboratory and animal model findings, and thirdly national authorities had approved such use. The objective in this case, was to reduce the risk to both patients and healthcare workers; and the team ensured that consent from patients was obtained, patients were monitored and the results documented and transmitted quickly to the medical and scientific community. This was a compassionate use protocol under regulatory and ethical control. Implementation was done in a stepwise fashion: efforts were made to identify the national principle investigator, then prepare and submit all the MEURI protocols, ensure that legal agreements are in place for the importation and cold chain requirements, and finally carry out GCP training. Efforts were made to engage all Ebola Treatment Centres (ETUs) stakeholders in the field, and agree on medical decision-making protocols with the ministry of health. Dr Castro-Rial and her team also ensured there was safe drug administration, good data management, and that they had a data-monitoring committee in place. The ethical approval was obtained 10 days after the outbreak started and clinical experts were then able to deploy to the field in order to assist the Ministry of Health with MEURI implementation. This required a coordinated effort, training ETU staff, and collaborative work in caring for patients, while assisting in gathering standard clinical data, including reporting serious adverse events (SAEs). In the DRC Ebola outbreak, treatment adopted under the MEURI protocol evolved into a randomised clinical trial. The results of the PALM trial indicated that four of the ‘unproved’ medications used under MEURI were more effective, than the other two licensed treatments; and recommendations as to their usage are now forthcoming. Dr Castro-Rial argued that this shows conclusively how the process of using ‘unproven’ interventions can be done ethically, and with all the key stakeholders involved, while preserving safety.
The role of monitoring in the usage of unproven interventions
The seminar then opened up for discussion. In regard to the safety aspects of using unproven interventions, Dr Bateman-House returned to her original point on capacity, which is particularly relevant in a public health emergency but also preparedness. However she put forward the question - what do you do if there’s no time for capacity-building? Unfortunately, if this is the case, there’s not much that can be done; proceeding without safeguards would be irresponsible. The MEURI guidelines are important because they specify what actions can be taken both before and during a public health emergency while ensuring safeguards are in place. Dr Mastroleo followed-up on this, adding that Dr Castro-Rial’s emphasis on ‘monitoring’ is in fact a key aspect of the MEURI framework and effective implementation. However, furthermore it can also act as a bridge to a clinical trial; there is a duty to do research during a public health emergency, this needs to be communicated and should form part of public health emergency response. Professor Upshur emphasised the value of data. Even if clinicians are placed in difficult situations where treatments for sick patients are unavailable, there is an obligation to collect data, and ensure any therapeutic intervention is documented, and can be evaluated accordingly. Dr Castro-Rial agreed, arguing that clinicians anchor themselves to evidence; and in the absence of evidence problems emerge. This was witnessed during Ebola and also COVID-19; without a guideline clinicians and public health authorities struggle. However, there are many ideas coming out, and if evidence isn’t there, then clinicians should be flexible and look to find it. However, any ‘unproven’ intervention must be done under a clinical trial, or monitored. She argued that the main conclusion from the Ebola outbreaks between 2014 and 2016, is that clinicians don’t have all answers: uncertainty is a fact when it comes to caring for and protecting patients.
How do you see the role of clinical ethical committees in evaluating this situation?
Dr Mastroleo directed attendees to the MEURI ethical framework, which contains a detailed exposition on the role of research ethical committees. However, recommendations are often non-specific emerging from different parts of the world, and from ethical committees which will have varying levels of complexity; therefore each committee must have capacity to evaluate what is being asked of them. Dr Castro-Rial reiterated this stating that the role of ethics committees depends on the country and the context. When there are strong national ethics committees in place this can actually delay implementation, but it also ensures that the Ministry of Health and authorities are included in the decision-making processes. This is particularly important in low-resource settings where a lot of damage has been done in the past by using therapeutics or trials without the Ministry of Health involvement.
To what extent have patients been engaged with in relation to the development of this framework, and secondly how do we manage public demand for unproven products when there are no proven treatment options in a public health emergency; for example the use of Ivermectin.
Dr Bateman-House returned to her original point of how do we define unproven medicine? In this case, medicines are normally assessed by regulators, but approval increasingly involves patient advocates or panels, who look at the trade-off of risks versus benefits. Dr Mastroleo said that the MEURI guidelines also contain recommendations on engagement. In the context of COVID-19, all governments displayed failures in communications. It’s important to also admit that there is uncertainty around the intervention in regard to its safety and efficacy. Unproven interventions which are not monitored or controlled can cause harm on an individual and social level, and this needs to be communicated, and enshrined within ethical guidelines.
Dr Castro-Rial argued that using 'unproven' clinical interventions during public health emergencies is an important area of study. We are finding medicine that is not based in evidence, because we don’t have it, and so we need to learn how to approach this within public health emergencies in a rational and safe way, while ensuring structures are in place to help us move forward in building evidence when we are facing new diseases. Dr Mastroleo spoke of the need to improve preparedness, and how we utilise unproven interventions both within public health emergencies, and between them. The pandemic reveals the structures we already had, and the absence or limitations of structures indicate the need for capacity-building in and between pandemics. Dr Bateman-House concluded by saying that the WHO guidance is a vital document, and something which can be used to start the pre-planning for emergent and non-emergent situations.