In this study, we described the characteristics and the motivational and decisional factors of SARS-CoV-2 clinical trial participants in the Netherlands. We also investigated whether answers were reported differently before and after participation.

We found that the majority of respondents were motivated by the desire to contribute to science or to helping the Netherlands. Financial compensation was classified as very or somewhat important by less than half of the respondents in a ranking of motivational factors and was the single most important motivational factor for only 20% of participants [10]. When deciding to take part in a trial, participants made a balanced decision involving trust in the study team, possible burdens, and the importance of the research question. Reported motivational and decisional factors did not change after participation.

These results highlight the extraordinary conditions of the SARS-COV-2 pandemic. Mixed motivations have been reported in previous studies as well but less pronounced than in the current instance [10, 12]. While competence and friendliness of the study team were identified as important decisional factors in the past [11], financial reward is often indicated as the main motivation for participating [11, 12]. In this regard, it is interesting that as many as 44.7% of our survey respondents would have participated in the clinical trial even without a financial compensation.

The question then arises of whether SARS-CoV-2 study participants fall into a special category of medical volunteers, with distinct and mostly selfless motivations and, if so, what accounts for these characteristics.

We postulate that the underlaying motivations of medical volunteers participating in any clinical trial are fundamentally the same. However, external circumstances may affect how motivational factors are weighted, amounting to a different decisional outcome depending on the situation. According to our hypothesis, the decision to participate in a clinical trial is compounded by three elements: the reward of participating, the cost of inaction, and the risk of suffering negative consequences from participation. If the sum of the rewards and the costs of inaction are higher than the risks, the decision will be in favor of participation, against it otherwise (Fig. 4).

Theoretical model of the decision-making process of medical volunteers. The sum of the rewards and the cost of inaction must exceed the risks for a healthy individuals to decide to take part in a clinical trial

The rewards of participating in a SARS-CoV-2 vaccination trial were high: besides the financial compensation, medical volunteers potentially derived a personal advantage from their participation, as it allowed them to be vaccinated before the rest of the population. Of course, it should be noted here that while benefit from participation in clinical trials may be an added bonus, it is never guaranteed and one should be careful not to introduce therapeutic misconceptions about the scope of any type of clinical research.

Secondly, the cost of inaction was high, as the pandemic was a very tangible threat that directly affected the lives of clinical trial participants. In line with this, the proximity of the threat also accounts for its perceived danger and urgency. This concept has been most famously described by Peter Singer’s drowning child thought experiment: humans feel more compelled to help when suffering is close by than when it is far removed [13, 14].

It is not surprising then that the volunteer-led initiative 1DaySooner, whose members advocate for participation in high-risk, high-gain challenge studies [15], was founded during the pandemic. 1DaySooner continues to exist even now, yet it was the immediacy of the threat that brought it to life.

Any altruistic motivations, that is, the desire to help others independently of one’s own gains [16], may also be considered an extension of this second postulate. In other words, the risk of inaction is determined by how heavily one weighs the lack of a cure for the disease under study. However, altruism remains a controversial philosophical and sociological concept and some have argued it to be a form of disguised egoism [17,18,19].

Finally, another factor that influences an individual’s decision to partake in a clinical trial is the perceived risk. Most SARS-CoV-2 vaccine trial participants described in the current study were not scared of being vaccinated and judged the risk of the study to be absent or moderate. It is doubtful whether someone convinced that vaccinations would harm them would have participated in any SARS-CoV-2 trial, no matter what the benefits.

It should be noted that the evaluation of each of the above-mentioned factors, namely the rewards, the cost of inaction, and the risks of participation, is subjective and highly dependent on personal beliefs and circumstances, which may be referred to as value system.

Comparing SARS-CoV-2 vaccination trials to the conceptual framework of other, “regular”, clinical trials shows how situational circumstances may affect the outcome of the decision-making equation.

Healthy individuals usually have little to no personal incentive for participating in clinical trials. The chances that they will directly benefit from the tested drugs is minimal and remote, making financial compensation the main reward. The risk of inaction is usually low for healthy individuals, as their lives are not directly affected by the outcome of the clinical trial. Conversely, the risk of participation is relatively high for healthy medical volunteers: if anything, they might be better off not taking part and avoiding the risk of side-effects.

In this model, financial compensation may be the only factor weighing against the risks and burdens of participation. We postulate that economic reward should not be considered an undue influence on participants, but rather a component of a weighted decision to do or do not take part in clinical research. While the absence of truly altruistic motivations may appear callous to some, it would be inappropriate to utter judgement. The framework presented herein is not meant as a moral guide but rather as a tool to understand human behavior.

The second research question concerned the recall bias of surveys administered after clinical trial participation: little change in answers was observed comparing the pre- and post-participation surveys. The participants’ judgement is unaffected by time and/or by the experience of the trial itself, further highlighting the consistency of our results over time.

The evaluation of the most important aspects of a clinical trial, are, among others, dependent on the education and information provided by the research team during the informed consent briefing. Providing extensive and adequate informed consent is of great importance to aid the potential participant in their decision to partake in the trial. Our study shows that participants do weigh the provided information carefully and that the outlined expectations corresponded to reality, emphasizing the importance of the informed consent procedure.

Respondents were participants of a number of different types of trials, ranging from phase 2 vaccine studies to post-licensure fractional dose immunization studies. This might induce response bias, if answers differ depending on trial. Another concern is that self-reporting respondents may not be completely honest [20]. However, the surveys were anonymous, thereby alleviating the pressure to answering in a socially desirable way.

This study shows that the SARS-COV-2 pandemic induced clinical trial participants to behave differently than previously observed [10, 21, 22]. We propose a theoretical framework to explain the decision-making process that leads healthy individuals to participate in clinical trials. This framework shows that the underlaying motivations of medical volunteers participating in any clinical trial are fundamentally the same, but that context determines actual behavior. The framework can be a starting point for further research whether medical volunteers can identify with it.

Moreover, we show that recall bias of questionnaires administered after a clinical trial is negligible and that the answers to such questionnaires may be considered reliable. Overall, the opinions and impressions of medical volunteers are not easily swayed by time and the experience of the trial itself.

Our results highlight that the agency of medical volunteers who freely decide to participate in a clinical trial should be recognized. Especially in high-risk, high-gain situations, medical volunteers may consider a variety of factors when deciding to participate in a clinical trial. Just as it is important that individuals are not coerced into partaking in research against their will, their informed decision to do so, should also be honored.