Background

Throughout the 2020 COVID-19 pandemic, reports about the provision of unproven and experimental interventions outside clinical trials were common. Such reports were especially prevalent in the early stages of the pandemic when no safe and effective treatments were available for COVID-19. Examples included experimental interventions being investigated in clinical trials, such as Remdevisir before it received an emergency authorisation, market approved medications being prescribed ‘off-label’ (e.g. hydroxychloroquine) as well as immunotherapy products (e.g. interleukin inhibitors and convalescent plasma) and highly experimental stem cell-based products being provided as an ‘innovative’ therapy. While the default position rightly restricted the use of these interventions to clinical trials, it was recognised that there would be situations where some patients would be unable to gain access to them – either because trials were not being conducted locally or, if they were, an individual patient may not meet the eligibility criteria or may not wish to participate.

In many cases, these practices were likely motivated by physicians who want to save lives and relieve the suffering of their patients. However, they were also controversial because the interventions lacked evidence of safety and efficacy for treating COVID-19 and, in some cases, deprived non-COVID-19 patients of (proven) drugs for treating their conditions (e.g. hydroxychloroquine for treating lupus). Critics were also concerned that widespread, uncontrolled access to unproven interventions outside of research may derail or prolong ongoing clinical trials by diverting limited resources. It may also undermine initiation of and recruitment for new trials, as well as consent and trust in research (National Academies of Sciences Engineering and Medicine 2017).

Some practitioners invoked the MEURI (Monitored Emergency Use of Unregistered and Investigational Interventions) framework of the World Health Organization (WHO) as justification for providing unproven interventions. MEURI is an ethical framework for developing a protocol to monitor the use of unproven medical interventions outside of research for therapeutic or preventive use during a public health emergency (Mastroleo, Smith, and The WHO MEURI Working Group 2020). MEURI was developed in response to the 2014-16 Ebola epidemic in West Africa, and was applied in infectious disease emergencies (WHO 2016) prior to COVID-19.

During the COVID-19 pandemic, the Pan American Health Organization (PAHO 2020) issued a document clarifying MEURI by categorising its requirements into features of justification; ethical and regulatory oversight; consent process; and contribution to the generation of evidence or knowledge. Notably, PAHO emphasises that while MEURI share common features of observational research, it should be applied only under exceptional circumstances i.e. access to unproven interventions outside clinical trials during an emergency situation should be provided only when clinical studies are unavailable or infeasible to initiate because of reasons such as an overwhelmed health system, lack of research capability or resources, insufficient patient numbers and so forth. Nevertheless, PAHO (2020) mandates that MEURI protocols must be reviewed by a research ethics committee or institutional review board (IRB), and must contribute to the generation of knowledge. This qualification could lead MEURI to be defined as research in some jurisdictions, triggering research regulatory requirements.

Applying MEURI as described above within the Singapore regulatory context would be legally and ethically problematic. Although the Singapore Medical Council (SMC) 2016 Ethical Code and Ethical Guidelines (ECEG) permits physicians to prescribe medications off-label and also to provide unproven interventions outside the context of formal research under certain circumstances as ‘innovative therapies’ the MEURI requirement to contribute to knowledge production through the monitoring, documenting, and sharing of results with the wider medical and scientific community may be viewed as an activity that the Human Biomedical Research Act (HBRA) 2017 defines as research. HBRA defines research as “any systematic investigation with the intention of developing or contributing to generalisable knowledge”. Whether monitoring, documenting, and sharing results with the scientific and medical community constitutes the development or contribution to generalisable knowledge is unclear, but if such activities fall within the scope of the law, they would require ethics review from an IRB.

Since COVID-19 had no known effective standard of care treatments at the time of the outbreaks in Singapore, any intervention aimed at treating the disease and not just the symptoms would fall within the SMC’s definition of an ‘innovative therapy’. These therapies may be provided outside formal clinical research when conventional therapy is unhelpful and “it is a desperate or dire situation” (Singapore Medical Council 2016b, sB6.4). In those circumstances, physicians should seek professional consensus on the use of the intervention in that particular clinical situation and obtain informed consent as appropriate. If no clinical trials or IRB-approved studies have been established in Singapore, then physicians would require guidance on when it would be ethically acceptable to provide various non-standard or experimental interventions in the treatment of moderate and severe COVID-19 disease. In view of such existing professional guidance, we propose the Professional Oversight of Emergency-Use Interventions and Monitoring System (POEIMS) as an alternative pathway to MEURI.

Ethical guidance for treating COVID-19 patients with POEIMS

POEIMS allows for the provision of interventions in public health emergencies that fall within the ECEG definition of innovative therapies and may be triggered in very limited circumstances where patient(s) have no other helpful options and are “in a desperate or dire situation”. In the context of COVID-19 pandemic, severely ill patients for whom an intervention may save their lives or ameliorate their pain and suffering, and who are not able to enrol in an IRB-approved study for any reason, may be judged to be in a sufficiently dire situation to justify providing the intervention solely as part of their clinical care. Patients with moderate disease who are at high risk of developing severe disease may also be considered, provided the individual patient’s best interest are clearly served by early intervention and when the potential risks are materially lower than the likelihood of averting progression to a severe state.

The CEC is preferred over an ad hoc committee convened for the purpose of reviewing such proposals as the latter would lack the continuity and training of an established CEC. It is also preferred over an institutional innovation ethics committee because it would not require creating an entirely new entity and the process can be folded into the existing committee’s scope of work. Although this requirement places additional demands on CEC members, many of whom are clinicians who are likely to be stretched in the context of a public health emergency, it is ultimately for the benefit of patients. To support these interventions, institutions or the relevant authorities should have in place specific requirements for notification of such plans for approval, while consideration of these requests should be expedited. They should also have in place mechanisms for reporting and monitoring.

Having met these criteria, physicians should be guided by the following:

Ethical justifications for POEIMS

The ethical justifications for POEIMS lie in the physician’s duty to provide care to patients that is in their best interests with professional oversight and support for learning health systems. Shared decision-making models would normally aim to establish whether an intervention meets that standard through physician advice and patient reflection on the goals of care, and what is achievable given their condition and the existing available treatments. However, professional advice is not based on the insights of a physician alone but is built on a larger body of peer judgment and evidence on the safety and efficacy of treatment options. At the same time, by definition, unproven or experimental interventions lack such an evidentiary framework and an individual physician may be mistaken in their judgment of the risks and benefits.

POEIMS provides safeguards for these epistemic limitations by requiring a clear protocol that helps promote rigorous, consistent applications of good practices, especially when multiple patients in similar situations may receive the same unproven treatment. In addition, review by a CEC provides the opportunity for broader peer input and feedback, minimising the impact of idiosyncratic judgments of individual physicians and bring to bear a larger body of experience and expertise to inform decision-making. Our proposal may be regarded as a modification of the Declaration of Helsinki (DoH) guidance on “Unproven interventions in Clinical Practice”, (World Medical Association 2018) which is not specifically directed at public health emergencies:

In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorised representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy.

POEIMS aims to protect patients from ineffective or harmful innovative therapies through its requirements for structured protocol and peer review. In the absence of a standard of care, as with unproven treatments, the above conditions help provide a substitute for systemic review by a group of peers and prevent limitations on the scope of treatments in circumstances where the risk-benefit ratio is most favourable.

Given that monitoring outcomes is an essential component of POEIMS, medical institutions have an obligation (qua advancing the best interests of all their patients) to future patients to learn from their experiences in using the interventions. Systematic monitoring facilitates internal evaluation of safety and efficacy of a given unproven protocol, information which may inform adjustment of future treatment applications. This is a very imperfect substitute for more rigorous evidence from clinical trials, and so institutions (and health systems more broadly) have an obligation to carry out clinical trials of unproven interventions as soon as feasible—a component that has recently been characterised as the duty to support learning health systems (London 2021). POEIMS aims to provide oversight and rigour for care in this context.

An alternative suggestion is to much more tightly restrict the application of unproven interventions outside formal research settings (Menikoff 2021). This may better advance the duty to support learning health systems than our proposal, insofar as it would push many more treatments into research contexts that would contribute to knowledge generation and further improve healthcare and health systems. However, such restrictions may conflict with physicians’ duty of care towards individual patients. There are myriad reasons why formal research may not be established in a given context beyond clinician and patient reluctance, including the availability of resources, expertise and institutional support. Restrictions on access do not address these barriers, and so will often result in no innovative treatment being provided at all rather than an innovative treatment within an approved study protocol. Our POEIMS proposal, by contrast, provides a balance between potentially conflicting duties of care and duties to support learning health systems.

Conclusion

We have proposed POEIMS as an ethical alternative to the provision of experimental interventions during public health emergencies outside of formal research settings based on the best interests of individual patients and commitments to learning health systems. The framework would only be triggered in very limited circumstances where there is an urgent unmet medical need and no standard of care interventions or authorised products are available for treating the disease, and when formal clinical studies cannot be set up for patients to access the intervention in a supervised trial setting.

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