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Bioethics Forum Essay

Navigating Ethics Review of Human Infection Trials With Zika

Human infection challenge studies, which deliberately expose healthy volunteers to disease-causing infectious agents under carefully controlled conditions, offer a valuable method of biomedical research aimed at efficient initial efficacy testing of vaccine candidates, among other possible uses. They can be controversial, however, often evoking the response, “How can researchers do that?” Although Nazi physicians conducted egregious human challenge experiments on concentration camp inmates, many valuable challenge studies have been ethically and safely conducted over the past 40 years in which healthy volunteers have been exposed to infectious conditions such as influenza, cholera, and malaria.  While these studies can produce temporary symptomatic distress, they have not to date been associated with lasting serious harms.

The planning of human challenge trials of infectious agents for which there is no currently effective and curative therapy calls for especially careful assessment. Such agents contrast influenza, which is usually self-limiting in healthy individuals, or cholera and malaria, for which known effective treatments are available.  Given the urgent need for a Zika vaccine, the National Institute of Allergy and Infectious Diseases decided to convene an ethics consultation, in which we participated, to review and provide recommendations on the possible conduct of a Zika virus human challenge study.  Exposure to Zika virus in healthy adults can cause serious harms, such as Guillian-Barre Syndrome, and no effective treatment is available.  Furthermore, infected individuals can transmit infection to others, and infection during pregnancy can result in severe neurological fetal abnormalities with life-long consequences.

We participated in that ethics panel, which issued recommendations following presentations of experts on pertinent scientific, regulatory, and ethical issues, thorough review of the limited ethics literature on human challenge trials, and extensive deliberation. The major recommendations were twofold:  in principle a Zika human challenge trial might be ethically justifiable, given adequate measures to protect human subjects and bystanders (who could become infected); and conducting a Zika challenge study was not justifiable at the time of our review, owing to lack of clear social value of the research in contributing to plans already underway to undertake field trials of vaccine candidates. Specifically, it was not clear that a challenge trial would sufficiently accelerate the development of an effective Zika vaccine to justify the risk to research participants and bystanders. The recommendations of the ethics panel and further reflections on the issues of bystander risk and social value were discussed in a recent article written by members of the panel and published in Science.

The recommendations of the ethics panel and the article in Science provoked strong negative reactions from two investigators who had developed preliminary plans to undertake a Zika human challenge trial, as reflected in a New York Times article.

One of the investigators declared: “It’s really insulting.  We’ve been painted as mad scientists who do horrible studies on human beings.  But we’re on top of all these risks.”  This is indeed a straw man.  The ethics panel, which was not charged with reviewing a particular research protocol of this or any other investigator, did not state or suggest that investigators who proposed conducting Zika human challenge studies were “mad scientists who do horrible studies on human beings”—a charge that would apply to Nazi physicians who conducted abusive experiments but not to any contemporary scientists undertaking a human infection challenge study under standard procedures of review by the NIH and an Institutional Review Board.  This perceived insult was belied by the judgment of the ethics panel that a Zika human challenge trial could be ethically justified in principle.

A second investigator was quoted as saying, “This ethics consultation was debilitating for the whole community.  It really slammed the door on progress.”  This comment also is off-base. The ethics panel was charged with making recommendations to the NIH generally about whether a Zika challenge trial could be ethically justified and if so under what conditions. It had no charge or authority to review any specific study nor to decide whether a future Zika human challenge study would, or would not, be undertaken. Stating that the stance of the ethics panel impeded “progress” further begs a key question that was at issue:  whether a proposed Zika human challenge study would have sufficient social value in guiding vaccine development in order to justify the exposure of human subjects or bystanders to greater than minimal risks of harm. In fact, exposures to bystanders could have major consequences for public trust in other challenge studies or other types of research, and thereby impede future progress. Finally, our panel also noted that this social value judgment was based on a snapshot of ongoing research in February 2017, and that this might change over time. The picture is different today.  We made clear in our Science article that as Zika vaccine trials become more difficult due to the sporadic and unpredictable outbreaks that now occur, a Zika human challenge study could emerge as having clear and considerable social value in current or future contexts.

We suggest some lessons for bioethicists specializing in research ethics from our experience on the Zika human challenge study ethics consultation. Research ethics has become associated primarily if not exclusively with protection of research subjects.  The focus needs to be expanded to also encompass concerns with risks to bystanders with the potential for being harmed from research via their contact with research subjects. More globally, research ethics should be understood as encompassing the goal of promoting socially valuable research and advancing the interests of populations through research and not just articulating constraints on research for the sake of protecting research subjects. The analysis and recommendations of the ethics panel that reviewed the prospect of a Zika human challenge trial deserve critical scrutiny and should be updated in light of changing information; mistaken judgments should be corrected and new facts may warrant revision. We encourage other bioethicists and investigators to engage in such critical scrutiny and be open to revising their views as new facts emerge in a spirit of respectful dialogue.

Franklin G. Miller, PhD, is professor of medical ethics in medicine at Weill Cornell Medical College and a Hastings Center Fellow. Anne Drapkin Lyerly, MD, MA, is professor of social medicine and associate director of the Center for Bioethics at the University of North Carolina at Chapel Hill.

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