Ebola Vaccine Trials: The Ethical Mandate for a Therapeutic Safety Net
Randomized controlled trials (RCTs) offer the fastest and most rigorous assessment of vaccine efficacy. Yet, they are only ethical if there is “clinical equipoise”—genuine uncertainty in the medical community regarding whether the experimental arm will do more good than harm relative to the control arm . We argue that Ebola vaccine RCTs can achieve clinical equipoise without sacrificing scientific rigor by providing enhanced supportive care and access to experimental therapeutics to trial participants who become infected.
Most discussions thus far have analyzed vaccine and treatment RCTs under a single ethical framework. Yet, there is a critical distinction: treatment RCTs investigate whether experimental treatments prevent death and require a relatively high CFR in the control arm to detect clinical efficacy (and we agree with previous arguments that this precludes equipoise ), whereas vaccine RCTs investigate whether experimental vaccines prevent infection and can evaluate protective efficacy regardless of the CFR. Thus, scientifically valid vaccine RCTs can and should minimize mortality risk by providing the best standard of care for any trial participant who develops Ebola virus disease, which we argue includes access to experimental therapeutics. Crucially, this would also reduce the difference in mortality risk between arms, thereby facilitating clinical equipoise (Figure).
Although patients treated to date with experimental drugs and convalescent blood products differ from other patients in important ways, there is suggestive evidence linking these treatments to better outcomes, even when compared to hospitalized individuals in West Africa who received intensive supportive care (Table S1). More importantly, the consistent use of experimental treatments in the US and Europe despite limited evidence, implies that the health community expects their benefits to outweigh potential side effects.
Including a “therapeutic safety net” in vaccine RCTs would facilitate clinical equipoise and fulfill the ethical mandate to provide trial participants in developing countries the standard of care in the sponsoring countries . Proposed Ebola vaccine RCTs anticipate only 30 to 60 infections before reaching their stopping criteria . Thus, the supportive care infrastructure and supplies of therapeutic drugs or blood products required to establish a therapeutic safety net should be attainable.
Figure: Example of a therapeutic safety net balancing risk in vaccine trials. Anticipated number of deaths among participants by trial arm in a hypothetical vaccine trial, with and without a therapy that reduces the case fatality rate by 70%. The therapeutic safety net reduces overall mortality and, notably, this substantially bridges the gap between the two arms. Following vaccine trial proposals , we assume that 30 participants will become infected before the trial reaches its stopping criteria. Other assumptions are explained in the supplementary code, available at http://ebola.ici3d.org/BMJ/equipoise.R
Steve E Bellan, PhD, MPH
Center for Computational Biology and Bioinformatics, The University of Texas at Austin, Austin, TX, 78712 USA
Juliet RC Pulliam, PhD
Dept. of Biology and Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
Prof. Jonathan Dushoff, PhD
Dept. of Biology and Institute of Infectious Disease Research, McMaster University, Hamilton, ON, L8S 4K1, Canada
Prof. Lauren Ancel Meyers, PhD
Dept. of Integrative Biology, The University of Texas at Austin, Austin, TX, 78712 USA
Santa Fe Institute, Santa Fe, NM, 87501, USA
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Competing interests: No competing interests