When UK authorities granted permission in October 2020 for the first controlled infection study to be carried out to test the anti-Covid-19 vaccine Oxford University had just developed, reactions ranged from disbelief to disapproval.
Yet this type of experiment, which exposes healthy volunteers to an infection to assess the efficacy of a vaccine or treatment (it is sometimes called a ‘human infection challenge’), is not just a widespread practice but also an irreplaceable one in clinical research.
But involving healthy people in biomedical research is not risk-free, as recent tragedies have shown. In what context are these healthy volunteers enlisted? What motivates them? And how are they protected?
The uncertainty of clinical research
In March 2006, the firm TeGenero sought to assess the tolerance of an antibody designed to fight diseases like rheumatoid arthritis, multiple sclerosis and some leukaemias. Initial results from animal testing had proved relatively safe, so the firm decided to test the new molecule on humans. For this, TeGenero enlisted six healthy volunteers. When the drug was first administered to them, all six quickly suffered multiple organ failure. These unexpected complications were later explained: the antibody that was tested stimulated T-Cells that had previously been activated by other infections. These T cells are thought to have migrated to healthy organs and damaged them.
Ten years later, in January 2016, a study commissioned by Portuguese firm Bial to test a molecule designed to relieve pain and anxiety had an even more dramatic outcome: one of the six healthy volunteers enlisted was admitted to hospital on the fifth day of receiving daily doses of the experimental drug. His condition worsened, prompting medical authorities to declare him brain dead the next day. He died a few days later.
These two examples are proof that biomedical research, by its very nature, leaves little clue about the benefits participants might gain from it. Yet we cannot deny the considerable scientific and social value of clinical research: it has helped to develop and greenlight many treatments and operations that have increased the quality and duration of countless patients’ lives.
But therein lies the issue: a patient supposedly knows what the purpose of the research into their own disease is, whereas ‘healthy’ people used in clinical research have different motivations and a different understanding of the research involved.
In what contexts does clinical research call on healthy volunteers?
In France, any research conducted on humans is referred to, in the country’s public health code, as ‘research involving human beings’ without prior distinction between an ill volunteer and a healthy one.
Beyond preventive trials and phase-1 clinical research of medical products specific to them, healthy volunteers take part in biomedical studies that can differ wildly from one to the other. Worldwide, most studies involving healthy volunteers assess ‘bioequivalence’. Such studies are carried out to show similarity between blood levels produced by pioneering medicines and their generic versions. They are mostly conducted by specialist firms (‘Contract Research Organisations’) for pharmaceutical companies.
A 2017 survey identified more than 1,000 studies involving molecules being administered to tens of thousands of healthy volunteers, especially in India, China, and North America.
Healthy volunteers can also be part of a cohort – a group of individuals who accept to be monitored, sometimes over several decades, to provide helpful data in epidemiology and disease evolution. Some cohorts have helped form stores of biological samples (‘biobanks’), which are subsequently used as benchmarks in clinical research.
The Pasteur Institute, for instance, has hosted the ICAReB platform since 2008. ICAReB stores biological samples from around 300 healthy donors. Other biobanks help to assess behavioural mechanisms. For example, the Paris Brain Institute hosts the PRISME platform, which lists around 2,000 volunteers available to help develop technological solutions that assess real-life behaviour in a range of settings (waiting room, confined environments, public spaces, etc.), among others.
In a different context, healthy volunteers also serve as ‘comparators’ in research monitoring the victims of the 13 November 2015 Paris terrorist attacks.
What are the different “checks” that control clinical research on healthy volunteers in France?
In line with the country’s public health code, any research conducted on humans in France is subject to rulings that ensure participants’ safety and the study’s relevance.
Just as in the case of ill volunteers, healthy individuals have to receive transparent, comprehensible information about how the study will unfold, and the risks involved. This helps formalise their consent. A medical check-up determines whether their participation complies with the criteria of inclusion and exclusion defined in the study’s formal procedure approved by France’s relevant regulatory bodies (research ethics board; ANSM, France’s public agency for assessing health risks from drugs). At any moment, a volunteer can choose to leave the study without having to justify their decision.
In France, healthy volunteers who take part in clinical research are registered in a national database used to track their participation, the amount they have received in compensatory payments, and their waiting period between two studies. A national database entitled VRB (a French acronym meaning ‘volunteers in biomedical research’) lists those who consent to take part in biomedical research. It is worth noting that France and the United Kingdom are the only countries in the world that have set up such a database. The measure is designed to avoid a trend in ‘career’ healthy volunteers, as has arisen in the US.
What motivates healthy volunteers?
Being a volunteer in a vaccine trial, a pharmacokinetic study (which examines the fate of a drug in the body) or a cohort gives the participant a sense of belonging to a high-minded community that helps further knowledge.
This kind of approach can be more natural to a volunteer whose everyday activity relates to a particular field of research, like a student in healthcare. Healthy volunteers can also be people with a loved one suffering from a disease – their discovery of clinical research, their awareness of related challenges and their desire to help advance these studies boost participation rates in clinical trials. Whatever a volunteer claims drives them, the importance of their commitment for society is far from trivial.
Some people claim they volunteer for clinical research out of altruism, but others do so to receive compensatory payments for taking part. Could financial vulnerability be the key factor driving some into volunteering? In France, there is a cap on the yearly amount of compensatory payments a volunteer may receive for the constraints they have to undergo. But for many people, this amount still represents a sizeable sum, especially for those who are in a precarious situation.
Lastly, it is worth noting that not all segments of the population are equally aware of clinical research, which calls into question the ability to make research results relevant to all.
Ethics and utilitarianism
It is even trickier to evaluate how financial vulnerability factors in a healthy volunteer’s motivation in countries with weak ethical controls, or even in developed countries with very liberal political systems. Such case-scenarios challenge the very notion of voluntary service, especially as some research conducted outside of adequate regulatory frameworks or on vulnerable populations in developed countries has created a climate of distrust in which healthy volunteers feel exploited.
A volunteer can be led to commit to a clinical study by believing the benefit they gain from taking part – whether it be income or access to primary healthcare in some economic contexts – outweighs any risk they are taking. Yet a volunteer’s vulnerable situation cannot be a criterion of exclusion from any research, as such exclusion would aggravate the volunteer’s vulnerability in two ways: materially, by stripping them of the benefit they expect, and symbolically, by stripping them of their freedom of choice.
Torn between utilitarian guilt and a desire to serve society, researchers are helpless in the face of this dilemma.
Reducing vulnerable situations
Though our societies have set standards of arbitration and validation through bodies that regulate research, healthy volunteers should be able to be truly free to decide whether to join the handful of people who take on a risk for the common good.
It is therefore crucial to reduce vulnerable situations so that ethical research can be conducted with respect for healthy volunteers. This can be achieved by helping them better understand the challenges of the research they will accept to contribute to, and better assess the risks they will be taking. Moreover, information provided to garner informed consent, a critical dimension of clinical research, should be tailored to potential cases of vulnerability – especially economic and educational – specific to healthy volunteers. Lastly, widespread global use of national databases, like those used in France and the UK, would help better regulate research that involves healthy volunteers and therefore protect them.
Exposing healthy volunteers to risks that are not always under control routinely calls into question the dilemma between research that can be very useful to many and a risk taken by a few. In the current pandemic, this dilemma has prompted France to give up on infecting healthy volunteers to test anti-Covid-19 vaccines.
François Bompart, chair of the access committee at the Drugs for Neglected Diseases Initiative (DNDi), a Swiss non-profit research organisation that develops treatments for neglected diseases, contributed to this article. The authors would also like to thank Mylène Botbol-Baum, Didier Dreyfuss, Christine Lemaitre, Pierre Lombrail, Flavie Mathieu, and Corinne Sebastiani, the other members of the working group ‘Health Research in Resource-Limited Countries’, part of the ethics committee of INSERM, a French public institute for health and medical research.
This text was published following activities developed as part of the European project ‘Creating and Enhancing TRUSTworthy, Responsible and Equitable Partnerships in International Research’. It was translated from the French by Thomas Young for Fast ForWord