Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

Abstract

The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24,900 cases and about 10,300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. However, non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret the results, and can also waste scarce intervention-related resources, making them profoundly unethical. Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. We present an overview of clinical studies registered at present at the four main international trial registries and provide a simulation on how adaptive RCTs can behave in this context, when mortality varies simultaneously in either the control or the experimental group.

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

“…The advantages of randomized studies have been discussed extensively by others. 5,21–23 True confidence in the findings of studies of treatments with potentially small-to-moderate effects on mortality is often enhanced by well-performed randomized trials; in their absence, there is a greater risk that such treatment effects may be masked by selection bias and confounding. Although a major strength of the PREVAIL II trial was its randomized design, its weaknesses include an open-label as opposed to double-blind design (i.e., potentially influencing observational bias at the bedside) and the early termination owing to the dramatic decline in the number of infected patients.…”

A Systematic Review of Ebola Treatment Trials to Assess the Extent to Which They Adhere to Ethical Guidelines

“…An argument against randomisation is that it may not be acceptable to the local community who, against the background of Ebola’s high mortality rate, may not understand why some people are being given a potentially promising treatment whilst others are not [54,55]. On the other hand, randomising minimises allocation bias and reduces confounding factors [56,57,58]. Arguably, in the context of this Ebola outbreak, any reasonable and robust study design, sensitive to local conditions and meeting other ethical standards might be regarded as acceptable [49,59].…”

Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine

“…While the declining numbers of cases may not permit direct measures of vaccine efficacy in human subjects [31,32], the current trials along with numerous ongoing and international Phase I and II trials using the ChAd3 Ebola vaccine (with or without MVA boosting) will support ultimate licensure of an Ebola vaccine for human use.…”