Vaccine testing for emerging infections: the case for individual randomisation

Abstract

During the 2014–2015 Ebola outbreak in Guinea, Liberia and Sierra Leone, many opposed the use of individually randomised controlled trials to test candidate Ebola vaccines. For a raging fatal disease, they explained, it is unethical to relegate some study participants to control arms. In Zika and future emerging infections, similar opposition may hinder urgent vaccine research, so it is best to address these questions now. This article lays out the ethical case for individually randomised control in testing vaccines against many emerging infections, including lethal infections in low-income countries, even when at no point in the trial do the controls receive the countermeasures being tested. When individual randomisation is feasible—and it often will be—it tends to save more lives than alternative designs would. And for emerging infections, individual randomisation also tends as such to improve care, access to the experimental vaccine and prospects for all participants relative to their opportunities absent the trial, and no less than alternative designs would. That obtains even under placebo control and without equipoise—requiring which would undermine individual randomisation and the alternative designs that opponents proffered. Our arguments expound four often-neglected factors: benefits to non-participants, benefits to participants once a trial is over including post-trial access to the study intervention, participants’ prospects before randomisation to arms and the near-inevitable disparity between arms in any randomised controlled trial.

Learning health systems, clinical equipoise and the ethics of response adaptive randomisation

“…For example, Eyal and Lipsitch define equipoise in these terms and then argue that it should be rejected as a requirement for research 33. This illustrates the importance  of clearly demonstrating the operational utility of clinical equipoise, as I am doing here.…”

Improving vaccine trials in infectious disease emergencies

“…Whatever the other virtues of the stepped-wedge and ring-vaccination designs, they are not ethically superior to individual randomization (24, 25). Just as an individually-randomized trial would withhold the experimental vaccine from members of the comparator group, the stepped-wedge and ring-vaccination designs withhold the experimental vaccine from members of the delayed group, albeit temporarily (25).…”

“…Fair or unfair, that disparity is inevitable whether control is temporal or spatial or by type of intervention or based on the difference between intervention and placebo. We have termed it the “near-inevitable disparity within all randomized controlled trials of new interventions.” Accepting randomized trials—as one should—is accepting this disparity (24). …”

“…Inasmuch as individual randomization reaches adequate sample size earlier than the cluster-randomized alternatives (24), experimental vaccines could therefore become available to controls in individually-randomized trials earlier than to ones in the cluster-randomized alternatives. Figure 1 captures this possibility.…”

“…Green designates having been vaccinated. Both trials begin at point A in time, and once data collection is over at the individually-randomized trial, at point B, access to the vaccine candidate can be offered to all its participants, at point C. That takes place past data collection in that trial, but chronologically before the vaccine candidate reaches all participants of the stepped wedge trial, at point D (24). …”