Individually-Randomized Controlled Trials of Vaccines Against the Next Outbreak

Guest Post: Nir Eyal, Marc Lipsitch

Paper: Vaccine testing for emerging infections: the case for individual randomisation 

The humbling experience of international response to Ebola taught the world a thing or two on preparing for Zika and for other emerging infections.

Some of those lessons pertain to vaccine development against emerging infections. One lesson was that vigorous vaccine development should start long in advance of outbreaks. CEPI, the Coalition for Epidemic Preparedness Innovations, was recently launched with an initial investment of half a billion US dollars from the Gates Foundation, Britain’s Wellcome Trust and the governments of Japan, Norway and Germany. There is also growing recognition that best practices on vaccine testing should be developed prior to outbreaks, from a study methodology viewpoint.

By contrast, in Zika, ethical guidelines on response in general and on an aspect of vaccine testing were created only once the pandemic erupted. Shouldn’t ethical disputes, e.g. on trial design for vaccine candidates, be ironed out in advance of emerging infections?

One persistent ethical question in vaccine testing pertains to individually-randomized control in efficacy trials. At the height of the 2014-5 Ebola outbreak, individually-randomized controlled trials were much maligned. Our paper at the Journal of Medical Ethics sets out to defend that approach for vaccine efficacy testing in emerging infections, including highly fatal and untreatable ones in developing countries.

Nearly everyone agrees that scientifically, individually-randomized controlled trials are the gold standard of clinical research. But during the Ebola outbreak, ethicists, leaders, and humanitarian workers opposed them. For testing vaccine against a highly fatal infection without approved drugs or vaccines, they deemed these designs unethical. In October 2014, Science Magazine reported that ‘Doctors Without Borders (MSF), which has treated more Ebola patients in West Africa than any other group, emphatically opposes [randomized controlled trials] in affected countries for either treatments or vaccines. MSF’s Annick Antierens, who oversees “investigational platforms” for experimental Ebola products, says “this cannot be defended ethically.”’

In advance of similar controversies for future outbreaks, we show that these ethical concerns about individually-randomized control are misplaced. Whenever individual randomization is feasible—and it often will be—it tends to save more lives than alternative designs. And for emerging infections, individual randomization also tends as such to improve care, access to the experimental vaccine, and prospects for all participants relative to their opportunities absent the trial. It does so no less than alternative designs that opponents proffered would. That obtains even under placebo control and without equipoise—requiring which would undermine not only individual randomization but also the alternative designs. Our arguments expound four often-neglected factors: benefits to nonparticipants, benefits to participants once a trial is over including post-trial access to the study intervention, participants’ prospects before randomization to arms, and the near-inevitable disparity between arms in in any randomized controlled trial.

Recommended reading:

  • Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014;384(9952):1423-24. doi: 10.1016/S0140-6736(14)61734-7 [published Online First: October 10, 2014]
  • Caplan AL, Plunkett C, Levin B. Selecting the Right Tool For the Job. American Journal of Bioethics 2015;15(4):4–10. doi: 10.1080/15265161.2015.1010993
  • Cox E, Borio L, Temple R. Evaluating Ebola therapies—the case for RCTs. The New England journal of medicine 2014;371(25):2350-1. doi: 10.1056/NEJMp1414145 [published Online First: 2014/12/04]
  • Ebola ca Suffit Ring Vaccination Trial Consortium. The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola. BMJ 2015;351:h3740. doi: 10.1136/bmj.h3740
  • Henao-Restrepo AM, Longini IM, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 2015;386(9996):857-66. doi: 10.1016/S0140-6736(15)61117-5
  • Joffe S. Evaluating Novel Therapies During the Ebola Epidemic. JAMA 2014;312(13):1299-300. doi: 10.1001/jama.2014.12867
  • Kass N, Goodman S. Trials tempered by compassion and humility. New York Times 2014 Dec 1.
  • Lipsitch M, Cowling BJ. Zika vaccine trials. Science Magazine 2016;353(6304):1094-95. doi: 10.1126/science.aai8126
  • Presidential commission for the study of bioethical issues. Ethics and Ebola: Public Health Planning and Response. Washington DC, 2015.
  • Lipsitch M, Eyal N, Halloran E, et al. Vaccine testing: Ebola and beyond. Science Magazine 2015;348(6230):46-48. doi: 10.1126/science.aaa3178
  • Rid A, Miller FG. Ethical Rationale for the Ebola “Ring Vaccination” Trial Design. American Journal of Public Health 2016;106(3):432-35. doi: 10.2105/AJPH.2015.302996
  • Wellcome Trust and Center for Infectious Disease Research and Policy (CIDRAP) EVTB. Plotting the Course of Ebola Vaccines: Challenges and Unanswered Questions was made possible through a joint 2016 [updated March 2016. Available from: http://www.cidrap.umn.edu/sites/default/files/public/downloads/ebola_team_b_report_2-033116-final.pdf accessed March 8 2017.