Q&A: Benefits of COVID-19 human challenge studies may ‘significantly outweigh’ the risks
As researchers work rapidly to develop vaccine candidates and therapeutics for COVID-19, examining the ethical issues related to studies in humans have become part of the process.
In a Personal View published in The Lancet Infectious Diseases, Euzebiusz Jamrozik, MD, FRACP, and Michael J. Selgelid, PhD, of the Monash Bioethics Centre and WHO Collaborating Centre for Bioethics at Monash University, examined relevant ethical considerations related to human challenge studies for SARS-CoV-2, the virus that causes COVID-19, including risks to participants and third parties and potential public health benefits. They defined human challenge studies as studies that “involve the intentional infection of research participants and can accelerate or improve vaccine development by rapidly providing estimates of vaccine safety and efficacy.”
“We argue that these human challenge studies can reasonably be considered ethically acceptable insofar as such studies are accepted internationally and by the communities in which they are done,” Jamrozik and Selgelid wrote, adding that the studies “can realistically be expected to accelerate or improve vaccine development, have considerable potential to directly benefit participants, are designed to limit and minimize risks to participants and are done with strict infection control measures to limit and reduce third-party risks.”
Healio spoke with Jamrozik about current ethical issues with COVID-19 research and important considerations when publishing studies in a pandemic environment.
Q: What was the impetus for this viewpoint?
A: Human challenge studies have been proposed as a means to accelerate COVID-19 vaccine development and to learn more about SARS-CoV-2 with respect to infection, immunity and transmission. Challenge studies have improved vaccine development for cholera and typhoid (among other pathogens) and were conducted with other coronaviruses at the U.K. Common Cold Unit up until 1990 — and yet challenge studies are sometimes ethically controversial. COVD-19 challenge studies are particularly controversial in part because of risks and uncertainties, especially in the context of a relatively new pandemic, yet many young healthy adults are ready to volunteer for such studies — and the risks in younger people appear to be much lower than in older people. COVID-19 challenge studies are also controversial because it takes time to set up a challenge study, including the time required to develop a challenge strain. During this time, standard vaccine field trials — which have already begun — might provide vaccine efficacy estimates without the need for challenge studies, so long as field trials are started at the right time in the right place so that enough field trial participants are infected during an epidemic.
There is now an increasing consensus that preparations should begin for COVID-19 challenge studies in case they are needed. In our viewpoint, we provide preliminary ethical analyses on a range of relevant issues. Among other things, the potential benefits and risks of challenge studies should be systematically assessed, including via modeling if required. These estimates should be reassessed if or when preparations for challenge studies eventually make them a feasible option. In addition to discussions of benefits and risks, our viewpoint covers some topics that have received less attention in other papers on the ethics of COVID-19 challenge studies, including enrollment of health care workers, self-experimentation and the potential risks of vaccine-enhanced disease.
Q: What advice do you have for researchers attempting to balance the rapid pace of COVID-19 research with the ethical issues inherent in human trials?
A: We should maintain high scientific and ethical standards during the pandemic, as recommended by recent WHO guidance, among other publications. This means striking a balance between the need for exceptionally careful study design, ethics review and public engagement where appropriate without unduly delaying potentially beneficial research. This applies to all relevant types of research — including, potentially, COVID-19 challenge studies.
Q: Are there ethical issues that you have observed with any recent studies related to COVID-19?
A: In general, one of the major research ethics issues so far in the pandemic is the issue of scientific standards. Lower standards sometimes result in poor-quality but highly publicized studies and have led to recent high-profile retractions. Poor-quality research sometimes involves risks and burdens for participants (and sometimes other patients) with little or no scientific or public health benefit. As a result, poor scientific practices ultimately undermine the ethical rationale for such research.
A second issue relates to the timing of treatment and vaccine trials with epidemics. Several studies have been prematurely stopped because enrollment was limited by the success of public health measures in reducing the number of new cases. The sporadic nature of epidemics (and public health responses) provide an additional ethical rationale for multicenter trials and might, in some cases, support the need for challenge studies — because vaccine field trials cannot be conducted in the context of public health lockdowns, for example.
A third issue relates to informed consent. Some commentators have claimed that participants in SARS-CoV-2 challenge studies cannot give informed consent, because not all risks are known (ie, there is considerable uncertainty regarding this novel virus). This concern might also apply to other kinds of COVID-19 research and it also applies, for example, to first-in-human phase I drug and vaccine research — which likewise involves considerable uncertainty and can lead to unforeseen harms. This in itself does not mean that the research is unethical or that volunteers cannot give informed consent — but it does require particularly careful consent practices to ensure that volunteers understand not only the risks involved but also the relevant uncertainties. Challenge studies routinely involve tests of understanding during the consent process as one type of safeguard, but others may also be warranted.
Q: Does pressure from the public play a role?
A: Many members of the public would like to see research produce treatments, vaccines and other interventions for COVID-19 as soon as possible. But maintaining public trust in research requires that research programs, whether challenge studies or other types of research, are conducted carefully and to high scientific and ethical standards. Such pressure should prompt scientists and regulators to find ways of rapidly designing and conducting important research without undermining these high standards.
Q: What is the take-home message for clinicians?
A: The public health benefits of COVID-19 challenge studies could significantly outweigh the risks to consenting volunteers, but challenge studies will take time to prepare. During this time, vaccine field trials should proceed, risks to young healthy adults should be better characterized, and there should be more public engagement and coordination of research (and related public health activities) so that all potentially useful research options are available. Like other types of pandemic research, the stakes are high, which is a good reason to uphold high scientific and ethical research standards.
- Applied Clinical Trials. Lessons from TGN 1412. http://www.appliedclinicaltrialsonline.com/lessons-tgn-1412. Accessed June 11, 2020.
- Epidemic Ethics. Resources. https://epidemicethics.tghn.org/resources/. Accessed June 11, 2020.
- Heriot GS, et al. medRxiv. 2020;doi:10.1101/2020.05.18.20106187.
- Human Challenge Studies in Endemic Settings: Ethical and Regulatory Issues. https://www.researchgate.net/publication/340224204_Human_Challenge_Studies_in_Endemic_Settings_Ethical_and_Regulatory_Issues. Accessed June 11, 2020.
- London AJ, et al. Science. 2020;doi:10.1126/science.abc1731.
- Rubin R. JAMA. 2020;doi:10.1001/jama.2020.9881.
- ScienceNews. Infecting people with COVID-19 could speed vaccine trials. Is it worth it? https://www.sciencenews.org/article/coronavirus-covid19-human-challenge-trial-infect-people-vaccine. Accessed June 11, 2020.
- Shah SK, et al. Science. 2020;doi:10.1126/science.abc1076.
- WHO. Global health ethics. https://www.who.int/ethics/publications/key-criteria-ethical-acceptability-of-covid-19-human-challenge/en/. Accessed June 11, 2020.