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Feature Infectious Diseases

Ebola: an opportunity for a clinical trial?

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4997 (Published 06 August 2014) Cite this as: BMJ 2014;349:g4997

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 [1]. 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 [2]), 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 [3]. Proposed Ebola vaccine RCTs anticipate only 30 to 60 infections before reaching their stopping criteria [4]. 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 [5], 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

1 Van der Graaf R, van Delden JJM. Equipoise should be amended, not abandoned. Clin Trials 2011;8:408–16. doi:10.1177/1740774511409600

2 Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014;384:1423–4. doi:10.1016/S0140-6736(14)61734-7

3 Angell M. The ethics of clinical research in the Third World. N Engl J Med 1997;337:847–9. doi:10.1056/NEJM199709183371209

4 Cohen J, Kupferschmidt K. Tough choices ahead in Ebola vaccine trials. ScienceMag 2014;:1–8.

5 GSK. Proposed Phase 2 Program for ChAd3 EBOV Vaccine Candidate. WHO Consultation http://www.who.int/entity/immunization/diseases/ebola/GSK_Phase_2_Progra...

6 Bah EI, Lamah M-C, Fletcher T, et al. Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea. N Engl J Med 2014;:141105140010007. doi:10.1056/NEJMoa1411249

7 Schieffelin JS, Shaffer JG, Goba A, et al. Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone. N Engl J Med 2014;:141029140036007. doi:10.1056/NEJMoa1411680

8 Ebola WHO, Team R, March O, et al. Ebola Virus Disease in West Africa - The First 9 Months of the Epidemic and Forward Projections. N Engl J Med 2014;:1–15. doi:10.1056/NEJMoa1411100

Competing interests: No competing interests

01 December 2014
Steve E Bellan
Postdoctoral Fellow
Juliet RC Pulliam, Jonathan Dushoff, Lauren Ancel Meyers
The University of Texas at Austin
1 University Station