Ethics of human interventional trials: From COVID19 to TB

For centuries, ethics has played a pivotal role in guiding the development and implementation of medical sciences, and it has become more important than ever, as medical technologies develop in an unprecedented pace in facing growing global health challenges. In the third thematic seminar of the year, Helen McShane gave us a glimpse of the potential value of human challenge trials, where healthy volunteers are purposively exposed to pathogens under carefully controlled clinical conditions; and Jonathan Pugh discussed the complex ethical issues behind these studies.

Helen described her team’s work on tuberculosis (TB) and COVID-19, two widely different infectious diseases of major global health importance. Despite the long medical history of fighting against TB, its typically decades-long latency and immunity-subversive nature, and the lack of appropriate immunity marker have prevented us from developing an effective vaccine against lung infection or transmission (although the existing BCG vaccine is great at preventing severe childhood infection). On the other hand, over two years into the COVID-19 pandemic, there remains ample uncertainties about the disease and pathogen (SARS-CoV2). Through human challenge trials, Helen’s team could generate important understanding on the development of the diseases and protective immunity. In particular, they build “human challenge models” by exposing healthy individuals to the pathogens under strictly controlled clinical environments, and obtained bio-samples to validate the infection and identify and measure key immunological markers over the course of disease development. These models could then form the basis to evaluate the effectiveness of future vaccines or treatments against immunity benchmark derived from the models.  

While the TB trials exposed participants to relatively harmless BCG, the highly contagious nature of COVID-19 demand careful protection of participants, research staff, and the study environment. For example, an extremely detailed informed consent process is needed, only ultra-healthy, low-risk volunteers can be recruited, and participants are isolated in negative pressure rooms and only contacted by staff with full protective equipment. Despite that, there has been heated debate about the risk and benefits of these trials, both within and beyond the academia. Against that backdrop, Jonathan discussed the ethical issues related to these trials through several key principles of research ethics: 

1. Social and Scientific value – the trial must have adequate potential value for science and/or the society, and it should be properly designed and supported that such values can be achieved.
2. Autonomy – researchers must ensure participants to have a sufficient understanding of the choice they are making. This demands a carefully designed informed consent process suitable for the target population. For novel pathogens like SARS-CoV2, researchers need to deliberate on what level of uncertainty about the risks is considered acceptable, and what constitute actual informed consent. 
3. Beneficence – researchers has a duty of care to the participants, and they must balance the necessary risks against the benefits achieved by the research. Before pursuing a human challenge trial, researchers must clarify whether the research questions could be equally well answered by less risky approaches. If it was deemed necessary, what can be done to minimise risks (e.g. select a less harmful strain of pathogens, adopt stringent infection control)? 
4. Justice – the benefits and burdens of research should be distributed fairly. Some population subgroups vulnerable (e.g. people from resource-limited communities) may be more to the disease of interest but also less likely to participate in research, while some others (e.g. pregnant women) are typically excluded from trials due to risk uncertainty. This could leave the findings and benefits from trials less generalizable to the less participated groups; but over engagement (e.g. provide monetary incentives) may also be viewed as taking advantage of less well-off individuals. 

As medical technologies advance, humans’ ability to pursue scientific knowledge will grow endlessly. Human interventional trials are uniquely valuable in medical research, but history have shown us how they could go horribly wrong if no appropriate ethical limits are in place (e.g. medical experiments conducted by Nazi doctors in WWII concentration camps). The increased accessibility of (false or distorted) information via the internet and emerging distrust in “experts” also warrant researchers to engage the public effectively with full transparency, and to establish necessary systems that can build confidence among the public. 

Peter Ka Hung Chan is a Research Fellow at Reuben College, and an Oxford British Heart Foundation Centre of Research Excellence Intermediate Transition Research Fellow in the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU).