The Ebola clinical trials: a precedent for research ethics in disasters

Abstract

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: (i) the specification of exceptional circumstances, (ii) the specification of unproven interventions, (iii) the goals of interventional research in terms of individual versus collective interests, (iv) the place of adaptive trial designs and (v) 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.

Keywords: Autonomy; Clinical trials; NGOs; Public Health Ethics; Research Ethics.

Figure 1

Eligibility of investigational interventions for clinical trials in Ebola virus disease (EVD) patients: an example of a risk–benefit matrix. A possible mapping scheme of risks/benefits is shown. Acceptable combinations were considered for two situations: (i) treatment of confirmed cases or post-exposure after high risk events (shaded area) and (ii) post-exposure after low risk events (bordered area). The vertical axis shows if evidence of efficacy (E) exists from: E1, human compassionate use (considering the number treated and expert judgement on plausibility of efficacy); E2, in vivo, non-human primate; E3, in vivo, non-primate; E4, cell culture: virus neutralisation or inhibition of replication; and E5, other in vitro assays (eg, pseudo typed virus, molecular assays). The horizontal axis shows if evidence of safety (S) exists from: S1, human use: repurposed drug marketed for another indication; S2, human trial with healthy volunteers: phase 1; S3, human compassionate use (considering number treated and expert judgement on evidence of safety); S4, in vivo, non-human primate; S5, in vivo, non-primate; and S6, in vitro demonstration that predictable toxicity is unlikely to occur (eg, cross reactivity of antibodies with human cell lines).