The ethical relevance of two types of adverse health effects on research bystanders as applied to HIV,mosquito bednet and organ transplant trials

When are clinical trials’ ethically impermissible because of their health effects on non-participants of research? This article assumes that adverse health effects on research non-participants are ethically relevant and define bystanders as research non-participants who suffer adverse health effects. However, there is an important ethical difference between two types of adverse health effects.

The first type of adverse effect involves harm to bystanders’ health. For example, if an HIV treatment-as-prevention trial (discussed by Bärnighausen and by Eyal and Wikler in the current issue) results in bystanders who have sex with trial participants being infected with a resistant strain of HIV only because of the trial, then those bystanders’ health has been harmed. Similarly, if a pregnant bystander is infected with Zika virus by a mosquito that became a carrier of the virus only because a research participant was intentionally infected in a Zika challenge trial, then that bystander’s health has been harmed by the researchers running the challenge trial. ¹

The second type of adverse effect involves the reduction of a distinct health benefit (e.g. of a course of treatment) to a bystander. For example, consider a donor lung intervention trial (discussed by Kimmelman and by Cohen in the current issue) that increases the cold ischemic time of donor kidneys as a side effect of that trial, with the only ethically relevant result of that increase being well-managed short-term non-toxic delayed graft function of those kidneys. The trial has arguably reduced the health benefit of each kidney transplant without harming the bystanders’ health (I assume here for clarity of the example that the increased ischemic time and delayed graft function does not lead to harmful consequences, such as acute rejection and patient death). ² This is because whether or not there was a trial, each successful kidney transplant is a health benefit to the recipient. However, each kidney recipient’s health is worse off than it would have been if the trial had not occurred and thus the cold ischemic time of the kidneys was not increased. That is, the magnitude of the kidney transplant health benefit was reduced by the trial. Another example of this second type is evident in chemical research. Certain chemicals and chemical byproducts, such as DDE (dichlorodiphenyldichloroethylene), have been shown to reduce the effectiveness of immune responses to vaccinations. ³ Clinical trials that reduce the effectiveness of vaccinations in bystanders through the production or distribution of such chemicals in the environment involve the reduction of a health benefit.

These two types of health effect are not mutually exclusive, as it is possible for a clinical trial to both harm the health of a bystander and cause a reduction in a health benefit. For example, consider trials utilizing video monitoring of mosquito bednet usage (discussed by Krezanoski and Haberer and by Fairchild in this issue). If concerns about privacy result in bednet non-usage whenever the bystander sleeps under a monitored bednet and this results in the bystander being infected with malaria or another mosquito-borne disease that they otherwise would not have been infected with, then the bystander’s health has been harmed. However, they have also had the health benefit provided by bednet protection reduced in a way analogous to the reduced vaccine effectiveness case above. Similarly, if a bystander who is infected by Zika due to the aforementioned Zika challenge trial is significantly less compliant with an otherwise unrelated course of beneficial medical treatment only due to their painful Zika symptoms, then the bystander has suffered both a harm to their health and a reduction in health benefit.

We have reasons to avoid both types of adverse health effects, but all other things being equal, the strength of those reasons vary. Both bioethicists and moral philosophers have recognized that our duties to refrain from harming others, especially without their consent, are typically more stringent than our duties to maximize the benefits we provide others.^4,5 This is reflected in maxims such as Primum non nocere: “Above all (or first) do no harm.” All other things being equal, if you must select from one of two options, either (a) inflicting one harm of a particular magnitude on an unrelated stranger or (b) reducing a benefit that unrelated stranger receives by the same magnitude, there is more ethical reason to select (b) over (a). These harms are especially important in clinical trials involving bystanders. After all, it is often costly, difficult, or unfeasible to identify, let alone obtain consent from, bystanders. Informed consent by those who have decisional capacity can make otherwise ethically wrong harms permissible and the absence of such consent makes such harms especially difficult to justify.

This general principle about the relative ethical stringency of harms and benefit reductions is applicable to the different types of adverse health effects for bystanders. All other things being equal, clinical trials that lead to harms to bystanders are harder to ethically justify than ones that lead to reduced benefits to bystanders. To be ethically justified, clinical trials of the first type require a better benefit/burden assessment than trials of the second type. Furthermore, if comparable results can be obtained with trials of both types, there is ethical reason to prefer trials that only lead to reduced health benefits to bystanders, even if it is somewhat costlier to run such a trial.

While avoiding harms is, in general, more ethically important than avoiding reductions in health benefit, both types of adverse health effect are ethically relevant. For example, if a donor organ intervention trial not only results in harms in some bystanders (e.g. transplantee death only due to acute rejection of the donated organ), but also reductions in health benefit in other bystanders (e.g. short-term delayed graft function or reduced graft survival time), it is ethically worse than a trial that only results in the aforementioned harms.

This article argued that different types of adverse health effects on bystanders are ethically relevant for the design and justification of clinical trials. The relative stringency of the duty to avoid harm makes it more ethically important, all other things being equal, to avoid harm rather than avoiding the reduction of health benefits. This is especially important as in many cases it is difficult to identify research bystanders who will suffer adverse health effects, let alone obtain their informed consent. In these cases, all other things being equal, we have ethical reason to design clinical trials that only involve reduced bystander benefits over trials that involve bystander harms. When such trials are not feasible and we are unable to get consent for the significant harms to bystanders, these harms must be outweighed by substantial social benefits in order for the trial to be ethically justified. How substantial the benefits need to be to outweigh the burdens will require a benefit/burden proportionality comparison. Furthermore, meeting this proportionality requirement is a necessary but not sufficient condition for the ethical justification of the trial. Ethical research design must not just be concerned with the magnitude of adverse health effects on research non-participants, but also the types of those effects.