Regulating impact on bystanders in clinical trials: an unsettled frontier

Abstract

This paper informally reviews key research ethics guidelines and regulations, academic scholarship, and research studies, and finds wide variety in how they consider risk to bystanders in medical research (namely, non-participants whom studies nevertheless place at risk). Some of these key sources give no or very little consideration to bystanders, while others offer them the utmost protection (greater than they offer study participants). This unsettled frontier would benefit from a deeper investigation of the ethics of protecting research bystanders.

Medical and scientific studies can adversely affect people who do not participate in them and are not afforded standard human subject protections—“bystanders”, in this symposium’s terminology.¹ This surprisingly common circumstance raises ethical and regulatory questions: What protections and consent process, if any, are owed to bystanders? Can risks to bystanders make a study impermissible? Who should regulate this area?

Research ethics guidelines, ethics scholars, and researchers have taken vastly different positions on these questions. Our review aims not to be comprehensive, but rather to reflect the range of views on bystander risk that co-exist in current scholarship, policy, and practice. We review: (1) research ethics guidelines that consider, or, alternatively, remain silent, on bystander protection; (2) academic scholarship that considers such demands; and (3) examples of studies that manifest one or another approach to this issue. Each section orders its examples approximately from most lenient to strictest, but that order should be taken with a grain of salt. For presentational simplicity, all are on a single continuum. While crude as a way to represent such differently authoritative sources as articles and guidelines, and while some of the sources probably supported certain causes of action for reasons beyond risks to bystanders, the simplified format may be helpful in illustrating the breadth of logical possibilities for positons on this topic that are occupied by at least one guideline, article, or research approach. The findings are summarized in Figure 1. Each index on that figure (e.g. “1b”, “3a”) corresponds to a bullet point in the summary list that follows here.

Figure 1:

What would different guidelines, academic articles, and trialists (as suggested by their decisions about examples of studies they conducted) demand in order to permit a study judged to pose more than minimal risk to bystanders? Guidelines are marked in bold to reflect their greater authority.

1. Research ethics guidelines

1a. 45 CFR 46:

US law governing federally-funded research explicitly defines its mandate as protection of research subjects, but not bystanders.² Therefore, US federal regulations provide no protection (with the exception of subjects’ fetuses, which are protected under subpart B).³

1b. The Declaration of Helsinki:

This document remains largely silent on bystander protections (setting aside general protection of “the environment” and of “groups involved in the research”).⁴

1c. The Nuremberg Code:

Article 4 of the Code tells investigators to avoid all unnecessary physical and mental suffering and injury, without explicit exclusion of suffering and injury to bystanders. Informed consent rights are clearly afforded exclusively to the research subject.^{2, 5–7}

1d. The Council for International Organizations of Medical Sciences:

These guidelines acknowledge some risks to bystanders, namely, that research may affect normal care in a community and that publication of study results may stigmatize and otherwise upset certain groups, but they recommend mere “sensitivity” to these risks. More emphatically, these guidelines demand respect, rights to “engagement,” and various benefits to host communities (not just to study subjects).⁸

1e. Tri-Council Policy Statement of Canada:

The Statement grants people whom we would call study bystanders protections typically granted to study participants. For example, it suggests addressing a wide variety of potential harms, ranging from physical injury to lab workers through inadvertent disclosure of genetic information to stigma. In response, the Statement often recommends community engagement and community consent.⁹

1f. Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials:

This Statement dramatically broadens the designation of research participants, to include (nearly) everyone potentially affected, and hence (nearly) all bystanders, at least in cluster randomized trials: “A research participant [in cluster randomized trials] can be identified as an individual whose interests may be affected as a result of study interventions or data collection procedures…”¹⁰ The Statement then lists what it counts as “affected as a result,” and the list includes impact mechanisms that CFR46 and many other documents would not count as sufficient for study participation.¹⁰

2. Academic scholarship

2a. Hausman 2007:

The author acknowledges study risks to bystanders, but cautions on grounds like academic freedom against extending bystander protections, at least during protocol review.¹¹

2b. Rid and Wendler 2011:

The authors view risks to bystanders simply as part of the social risk that risk-benefit evaluations in clinical trials should consider.¹²

2c. Farquhar et al 2017:

The authors address the public health risk posed by some studies (e.g. laboratory “gain of function” studies) and recommend that researchers be permitted to conduct them so long as they or their funding bodies financially internalize the public health (i.e., bystander) risk. The authors thereby appear to hold that consent from bystanders is unnecessary.¹³

2d. Barker and Polcrack 2001:

Writing on studies of xenotransplantation, the authors argue that because there are potential significant risks of zoonotic disease transmission to the community, xenotransplant trials must have community approval before proceeding.¹⁴

2e. Battin et al 2009:

Writing on infectious disease studies that pose substantial risks to “statistical” bystanders, but not to anyone identifiable in advance, the authors recommend obtaining bystander community consent.²

2f. Resnik and Sharp 2006:

Writing on moderate risk to bystanders, the authors recommend that studies undertake risk-minimization measures, ensure public disclosure, and in some cases, obtain “permission” from bystanders—presumably, assent rather than fully-fledged informed consent.⁵

2g. Battin et al 2009:

Writing on infectious disease studies that pose substantial risks to identifiable bystanders (see above on their position on nonidentifiable bystanders), the authors recommend mitigating these risks (e.g. by urging safe sex practices) and obtaining fully-fledged informed consent from bystanders before conducting the study. Where bystander consent cannot be obtained, they add that the human subject who is the vector for potential disease transmission must be excluded from participation.²

2h. Kimmelman 2007:

Early work on risk to bystanders recommends disclosure of that risk whenever possible and, if the risk is high, informed consent when practicable.^{1, 6} The possibility that a study could be blocked for being too risky for bystanders, even with consent, remains open—a position one step more protective than merely demanding informed consent, and open to treating bystanders as full participants.^{1, 6}

2i. National Academy of Sciences 2017:

A recent report from the National Academy of Sciences, expounded in a case discussion by Jonathan Kimmelman and I. Glenn Cohen in this symposium, proposes that when a deceased organ donor is administered an experimental intervention to improve graft viability for a particular organ, recipients of other organs from that donor, who are not studied and who would count as research bystanders, be treated as though they were study subjects.¹⁵

2j. Evans et al 2015:

Addressing experiments on influenza that risk an accidental pandemic of a strain created in the laboratory, the authors, who emphasize that these studies do not involve actual human subjects, suggest treating victims of adverse public health impact as one would human subjects.¹⁶

2k. Shah et al 2017, 2018:

A recent committee convened by the US National Institute of Allergy and Infectious Disease to address the ethics of Zika challenge studies concluded that, unless such studies can virtually eliminate risk of harming sex partners, fetuses, and others from horizontal or vertical transmission of Zika, these studies should generally not be pursued. In this instance, bystanders were arguably given greater protection than study participants, perhaps because participants had consented.^{17, 18}

2l. Resnik and Sharp 2006.

Writing on serious risk to bystanders, these authors (whom we cite above for their position on another circumstance) recommend that studies ought not to proceed—even where risk has been minimized (yet remains high) and where bystanders consent to it.⁵

3. Examples of studies

3a. Many contemporary human gene transfer studies use viral vectors to deliver a modified gene. People living in proximity of the study participant may incur a theoretical risk from the virus or from horizontal gene transfer. The consent or assent of these bystanders is rarely if ever sought, as either individuals or communities.⁵ However, to protect bystanders who might come in contact with vectors through sexual activities, many trial protocols urge use of barrier contraception among research subjects.

3b. In 2016, release of genetically-modified mosquitoes to fight Zika, Dengue and other endemic diseases in Key Haven, Florida was subjected to a nonbinding referendum of local residents. A majority of the county voted in favor, but a majority of those in the study site itself (the island of Key Haven) voted against, leaving the next steps uncertain. This suggests that community approval can matter to a study’s sponsor or to local or national authorities.^{19, 20}

3c. In the historical debate on use of a live polio vaccination (which risks viral shedding to others from the patient) vs. a killed-virus vaccine (that involves no shedding), Jonas Salk, as well as Raisa Deber, Goel Vivek, and others, argued that causing harm to bystanders (e.g. unvaccinated relatives) is unjustified, even as the byproduct of an approach that minimizes polio overall. This was in part because of lack of informed consent to this risk exposure—suggesting that in a trial setting, bystanders at similar risk would have informed consent rights.^{2, 21}

3d. In this symposium, Paul Krezanoski and Jessica Haberer describe how a research team ruled out the use of invasive technologies for monitoring usage of mosquito nets in subjects’ houses. A central reason for this decision was the privacy impact on house guests—a category of bystanders—and not only the impact on study subjects themselves. Indeed, in this instance, bystanders seem to have received greater protection even compared to participants, whose exposure was allowed, perhaps on the ground that bystanders had not consented to that exposure.

3e. Many contemporary studies that would jeopardize any fetus, e.g. Zika challenge studies and HIV studies involving antiretroviral treatment interruption, exclude pregnant women (and sometimes, women of reproductive age who will not use two forms of contraception), primarily to protect fetuses from harm. This absolute exclusion seems to disallow even participation with the consent of the bystander’s (namely, the fetus’s) surrogate decision maker (namely, the pregnant woman).²²

Discussion

As Figure 1 shows, different regulatory documents, articles, and trialists deal in radically varying manners with the ethical and regulatory challenge of bystander impact and risk in clinical trials. Approaches vary from the wholly liberal, which does not apply regulatory rules to even severe risk to bystanders, to the wholly protective, which can regulate bystander risk even more than risk to study participants.

This disagreement probably reflects, in part, the limited attention that these considerations have received from bioethicists and policy-makers, except in a few waves mentioned above, especially one that lasted from 2005 till shortly later.¹ While wide disagreement is common in ethics, a sustained, comprehensive ethical theory on how to handle bystander impact and risk is currently lacking. This unsettled frontier would thus benefit from a deeper investigation of the ethics of protecting research bystanders. The case discussions that follow hopefully contribute to this aim, and more writing on this question would contribute further.

We have informally reviewed authors’ statements about multiple circumstances, e.g. about studies that involve high risk or identifiable victims and ones that involve moderate risk, or merely statistical victims. It is conceivable that, had our domain been classified more finely and limited to one type of circumstance only, greater consistency would surface. For example, based on the work so far, we cannot rule out the possibility that all authors would agree that for severe risks in identifiable individuals, the right regulatory approach is X and for merely moderate risks in populations, the right approach is Y. However, note some discrepancies about the same circumstance type, for example, between authors who, across all trial types, recommend informed consent rights or IRB review for certain bystanders, and other authors, who rule them out.

It is also possible that some of these sources recommended this or that practical approach for reasons other than bystander rights, e.g. participant rights or the protection of public trust. But in some cases, the sources give their reasoning and it pertains to bystanders.

Summary

Our informal review finds that the regulations, scholarship, and examples of studies above cover the entire continuum between the extremes of possible approaches to bystander impact in research studies. That a widely endorsed policy response to bystander risk has not emerged suggests that bystander risk has yet to capture the sustained attention of bioethicists and policy-makers. It is time to bring this open frontier into full view. A comprehensive account is needed of when, if ever, risks to bystanders make research activities illegitimate; and of what provisions, if any, may overcome this tendency. The case discussions that follow seek to energize, enrich and start identifying relatively settled points in that coversation.