Deliberate Microbial Infection Research Reveals Limitations to Current Safety Protections of Healthy Human Subjects

Here we identify approximately 40,000 healthy human volunteers who were intentionally exposed to infectious pathogens in clinical research studies dating from late World War II to the early 2000s. Microbial challenge experiments continue today under contemporary human subject research requirements. In fact, we estimated 4,000 additional volunteers who were experimentally infected between 2010 and the present day. We examine the risks and benefits of these experiments and present areas for improvement in protections of participants with respect to safety. These are the absence of maximum limits to risk and the potential for institutional review boards to include questionable benefits to subjects and society when weighing the risks and benefits of research protocols. The lack of a duty of medical care by physician–investigators to research subjects is likewise of concern. The transparency of microbial challenge experiments and the safety concerns raised in this work may stimulate further dialogue on the risks to participants of human experimentation.     

A Social Psychological Perspective

Ethics is normative; ethics indicates, in broad terms, what researchers should do. For example, researchers should respect human participants. Empirical study tells us what actually happens. Empirical research is often needed to fine-tune the best ways to achieve normative objectives, for example, to discover how best to achieve the dual aims of gaining important knowledge and respecting participants. Ethical decision making by scientists and institutional review boards should not be based on hunches and anecdotes (e.g., about such matters as what information potential research participants would want to know and what they understand, or what they consider to be acceptable risks). These questions should be answered through empirical research. Some of the preceding articles in this special issue illustrate uses of empirical research on research ethics. This article places empirical research on research ethics into broader perspective and challenges investigators to use the tools of their disciplines to proactively solve ethical problems for which there currently exist no empirically proven solutions.     

Empirical research on research ethics

Ethics is normative; ethics indicates, in broad terms, what researchers should do. For example, researchers should respect human participants. Empirical study tells us what actually happens. Empirical research is often needed to fine-tune the best ways to achieve normative objectives, for example, to discover how best to achieve the dual aims of gaining important knowledge and respecting participants. Ethical decision making by scientists and institutional review boards should not be based on hunches and anecdotes (e.g., about such matters as what information potential research participants would want to know and what they understand, or what they consider to be acceptable risks). These questions should be answered through empirical research. Some of the preceding articles in this special issue illustrate uses of empirical research on research ethics. This article places empirical research on research ethics into broader perspective and challenges investigators to use the tools of their disciplines to proactively solve ethical problems for which there currently exist no empirically proven solutions.     

What makes placebo-controlled trials unethical?

The leading ethical position on placebo-controlled clinical trials is that whenever proven effective treatment exists for a given condition, it is unethical to test a new treatment for that condition against placebo. Invoking the principle of clinical equipoise, opponents of placebo-controlled trials in the face of proven effective treatment argue that they (1) violate the therapeutic obligation of physicians to offer optimal medical care and (2) lack both scientific and clinical merit. We contend that both of these arguments are mistaken. Clinical equipoise provides erroneous ethical guidance in the case of placebo-controlled trials, because it ignores the ethically relevant distinction between clinical trials and treatment in the context of clinical medicine and the methodological limitations of active-controlled trials. Placebo controls are ethically justifiable when they are supported by sound methodological considerations and their use does not expose research participants to excessive risks of harm.     

Risk and Trust in Public Health: A Cautionary Tale

The leading ethical position on placebo-controlled clinical trials is that whenever proven effective treatment exists for a given condition, it is unethical to test a new treatment for that condition against placebo. Invoking the principle of clinical equipoise, opponents of placebo-controlled trials in the face of proven effective treatment argue that they (1) violate the therapeutic obligation of physicians to offer optimal medical care and (2) lack both scientific and clinical merit. We contend that both of these arguments are mistaken. Clinical equipoise provides erroneous ethical guidance in the case of placebo-controlled trials, because it ignores the ethically relevant distinction between clinical trials and treatment in the context of clinical medicine and the methodological limitations of active-controlled trials. Placebo controls are ethically justifiable when they are supported by sound methodological considerations and their use does not expose research participants to excessive risks of harm.     

A framework for risk-benefit evaluations in biomedical research

Essentially all guidelines and regulations require that biomedical research studies have an acceptable risk-benefit profile. However, these documents offer little concrete guidance for implementing this requirement and determining when it is satisfied. As a result, those charged with risk-benefit evaluations currently assess the risk-benefit profile of biomedical research studies in unsystematic ways, raising concern that some research participants are not being protected from excessive risks and that some valuable studies involving acceptable risk are being rejected. The present paper aims to address this situation by delineating the first comprehensive framework, which is based on existing guidelines and regulations as well as the relevant literature, for risk-benefit evaluations in biomedical research.     

Using the CABLES model to assess and minimize risk in research: control group hazards

CABLES is both an acronym and metaphor for conceptualizing research participation risk by considering 6 distinct domains in which risks of harm to research participants may exist: cognitive, affective, biological, legal, economic, and social/cultural. These domains are described and illustrated, along with suggestions for minimizing or eliminating the potential hazards to human participants in biomedical and behavioral science research. Adoption of a thoughtful ethical analysis addressing all 6 CABLES strands in designing research provides a strong protective step toward safeguarding and promoting the well-being of study participants.     

Should protections for research with humans who cannot consent apply to research with nonhuman primates?

Research studies and interventions sometimes offer potential benefits to subjects that compensate for the risks they face. Other studies and interventions, which I refer to as “nonbeneficial” research, do not offer subjects a compensating potential for benefit. These studies and interventions have the potential to exploit subjects for the benefit of others, a concern that is especially acute when investigators enroll individuals who are unable to give informed consent. US regulations for research with human subjects attempt to address this concern by mandating strict protections for nonbeneficial research with subjects who cannot consent. Typically, humans who cannot consent, such as children, may be enrolled in nonbeneficial research only when it poses low risks and has the potential to gather information of sufficient value to justify the risks, an appropriate surrogate gives permission on the individual’s behalf and the individual agrees (assents). In contrast, US regulations for nonbeneficial research with nonhuman primates do not include these protections, even though it too involves subjects who cannot consent and who face risks for the benefit of others. Is this difference in regulatory protections justified? Or does the principle of fairness—treat like cases alike—imply that regulations for nonbeneficial research with nonhuman primates should include protections similar to those that apply to nonbeneficial research with humans who cannot consent?     

THE SCIENTIST AS STATESMAN: BIOLOGISTS AND THIRD WORLD HEALTH

One of the most threatening problems the world faces is the growing poverty crisis and the related human rights inequalities and the spread of diseases in underprivileged areas. Human rights and relief organizations try hard to contain the devastation of these interconnected difficulties. What is the role of the biomedical scientist in this endeavor? The challenges that biomedical scientists face in their research lead us to question whether scientists can go beyond the time‐consuming realm of experimental investigation and engage the issues of society in a more public way. I suggest how the scientist's role can be expanded in our complex and precarious world, introducing the idea of the modern biomedical researcher as scientist, scholar‐philosopher, and statesman for the scientific community and the larger human rights community. I provide examples of where the scientist can interface with human rights organizations, medical doctors, political and civic leaders, and the science‐religion dialogue. My argument reveals the emerging role of the biomedical scientist as one of public service in addition to and beyond the realm of the experimental investigator. This role, however, is formidable, and I list some of the obstacles it entails.     

DNA patents and scientific discovery and innovation: Assessing benefits and risks

This paper focuses on the question of whether DNA patents help or hinder scientific discovery and innovation. While DNA patents create a wide variety of possible benefits and harms for science and technology, the evidence we have at this point in time supports the conclusion that they will probably promote rather than hamper scientific discovery and innovation. However, since DNA patenting is a relatively recent phenomena and the biotechnology industry is in its infancy, we should continue to gather evidence about the effects of DNA patenting on scientific innovation and discovery as well the economic, social, and legal conditions relating to intellectual property in biotechnology. We should give the free market, the courts, researchers, and patent offices a chance to settle issues related to innovation and discovery, before we seek legislative remedies, since new laws proposed at this point would lack adequate foresight and could do more harm than good. However, we should be open to new laws or regulations on DNA patents if they are required to in order to deal with some of the biases and limitations of the free market.     

Well-Being and Fairness

The article explores the interaction of two, potentially clashing, considerations, each reflecting a different conception of fairness concerning the resolution of interpersonal conflicts. According to the Equal Chance Principle, the harm for each person should be minimized in a significant and (roughly) equal degree; when this is impossible, each person should be accorded the highest possible equal chance to avoid the harm. According to the Importance Principle, the danger to the person who would otherwise suffer the more serious harm should be prevented. An erratum to this article is available at .     

Variables influencing the neural correlates of perceived risk of physical harm

Many human activities involve a risk of physical harm. However, not much is known about the specific brain regions involved in decision making regarding these risks. To explore the neural correlates of risk perception for physical harms, 19 participants took part in an event-related fMRI study while rating risky activities. The scenarios varied in level of potential harm (e.g., paralysis vs. stubbed toe), likelihood of injury (e.g., 1 chance in 100 vs. 1 chance in 1,000), and format (frequency vs. probability). Networks of brain regions were responsive to different aspects of risk information. Cortical language- processing areas, the middle temporal gyrus, and a region around the bed nucleus of stria terminalis responded more strongly to high- harm conditions. Prefrontal areas, along with subcortical ventral striatum, responded preferentially to high- likelihood conditions. Participants rated identical risks to be greater when information was presented in frequency format rather than probability format. These findings indicate that risk assessments for physical harm engage a broad network of brain regions that are sensitive to the severity of harm, the likelihood of risk, and the framing of risk information.     

Ethical analysis of research partnerships with communities

Community-researcher partnerships constitute one of the most important recent developments in biomedical ethics. The partnerships protect vulnerable communities within which research is conducted and help ensure that the communities benefit from the research. At the same time, they embody deep, core values about the social nature of persons and the value of community that significantly modify the radical individualism too often associated with the prevailing concepts of autonomy and respect for persons. This article examines the burgeoning literature on community-researcher partnerships to identify the main ways of thinking ethically about the obligations of investigators and the roles and rights of communities in scientific research. The paper helps to uncover the deep commonalities and differences that mark the current debate in this emerging arena of research ethics, a debate over the social nature of persons that is beginning to influence the understanding of other bioethical issues.     

Strategies to minimize risks and exploitation in phase one trials on healthy subjects

Most of the literature on phase one trials has focused on ethical and safety issues in research on patients with advanced cancer, but this article focuses on healthy, adult subjects. The article makes six specific recommendations for protecting the rights and welfare of healthy subjects in phase one trials: 1) because phase one trials are short in duration (usually 1 to 3 months), researchers should gather more data on the short-term and long-term risks of participation in phase one studies by healthy subjects; 2) researchers should develop strict inclusion/exclusion criteria that exclude unhealthy or vulnerable subjects, such as decisionally impaired people, in phase one studies; 3) subjects should not participate in more than one phase one study at the same time and should wait at least 30 days between participating in different studies; 4) researchers should develop a database to keep track of phase one participants; 5) subjects should be guaranteed a minimum wage equivalent to the equivalent type of unskilled labor, but there should be no upper limits on wages; and 6) subjects should be allowed to engage in collective bargaining with research sponsors.     

Ethics -- perceived or reasoned from principles?: a rejoinder to Korn, Huelsman, and Reed

In response to Korn, Huelsman, and Reed's (1992) question, "Who defines those interests, and how serious must the setback be?" (p. 126), we argue that a wrongful (unjust) harm (a setback of interest) is not equivalent to a hurt (a temporary distressing mental state) and that the interests of importance are welfare interests (general means to our ulterior aims), not just a desire to avoid unpleasant mental states (hurts). To set back a welfare interest is to reverse its course or to impede, thwart, defeat, or doom it. It is the primary responsibility of the investigator to define both welfare interests and the risk of harm. An informed consent -- one with substantial understanding, in substantial absence of control by others, and given intentionally -- allows participants to autonomously authorize participation in research, including their toleration of acts of mental discomfort or distress during an experiment. Not only were our participants not wrongfully harmed, they benefited and were willing to volunteer for future research. No strong evidence has been advanced or linked to guided imagery in a way that would justify its restraint; to so claim evokes a standard of legal paternalism that fails to respect participants' competence and autonomy to choose to participate in research on rape using guided imagery.     

Active SETI and the Problem of Research Ethics

This article argues that research involving active SETI, or sending messages toward possible extraterrestrial intelligence (METI), is not ethically justifiable. As a way of working some of the ethical problems associated with METI, I approach the sending of a message from the perspective that it represents a research endeavor involving sentient beings and therefore, should undergo review by a university institutional review board (IRB). As such, METI should be expected to meet several criteria expected by IRBs as being necessary components of ethically justifiable research. By considering issues of proportionality, justice, informed consent, the likely success of obtaining desired results, and necessity and considering risks and benefits to research subjects, as well as the mandate to do no harm, it is evident that METI does not meet the requirements for ethical research on human subjects and, thus, should not be considered ethical when it comes to nonhuman sentient beings.     

Ethical Considerations for Volunteer Recruitment of Visual Prosthesis Trials

With the development of visual prostheses research from the engineering phase to clinical trials, volunteer recruitment for the early visual prosthesis trials needs to be carefully considered. In this article, we mainly discuss several issues related to volunteer recruitment that had posed serious challenges to the visual prosthesis trials, such as low rates of participants, high expectations and underlying motivations to participate in the visual prosthesis trials as well as the importance of informed consent. When recruiting volunteers for visual prosthesis implants, it is critical that the visual prosthesis researchers should not only take into account the patient’s expectations and motivations, but also make the patients fully aware of the possible benefits and risks involved with their participation, and help patients establish realistic expectations for the early phase of visual prosthesis implantation. Based on these considerations to the challenges, eligible volunteers may be recruited in the preliminary stages of visual prosthesis trials.     

Innovative Practice,Clinical Research,and the Ethical Advancement of Medicine

Innovative practice occurs when a clinician provides something new, untested, or nonstandard to a patient in the course of clinical care, rather than as part of a research study. Commentators have noted that patients engaged in innovative practice are at significant risk of suffering harm, exploitation, or autonomy violations. By creating a pathway for harmful or nonbeneficial interventions to spread within medical practice without being subjected to rigorous scientific evaluation, innovative practice poses similar risks to the wider community of patients and society as a whole. Given these concerns, how should we control and oversee innovative practice, and in particular, how should we coordinate innovative practice and clinical research? In this article, I argue that an ethical approach overseeing innovative practice must encourage the early transition to rigorous clinical research without delaying or deferring the development of beneficial innovations or violating the autonomy rights of clinicians and their patients.     

Beyond physical harm: how preference for consequentialism and primary psychopathy relate to decisions on a monetary trolley dilemma

When is it appropriate to harm a single person to help multiple others? Psychologists have investigated this question through the study of hypothetical “trolley” dilemmas involving extreme physical harm life-or-death situations that contrast outcome-focussed, consequentialist moral reasoning with principle-focussed, deontological moral reasoning. The present studies investigate whether participants’ preference for consequentialism generalises across domains. We administered traditional physical harm dilemmas as well as a trolley-type dilemma involving monetary harm. Across four studies (N?=?809), an internal meta-analysis demonstrated that participants’ responses to the traditional dilemmas predicted their responses to the monetary dilemma. Additionally, previous research has uncovered that primary psychopathy predicts consequentialist responses on physical harm dilemmas. The current work uncovers that this association does not generalise to monetary harm dilemmas, suggesting that the association between primary psychopathy and consequentialist reasoning is not related to consequentialist reasoning per se, but to the idiosyncrasies of traditional harm-centric trolley dilemmas instead.     

Through the Community Looking Glass: Reevaluating the Ethical and Policy Implications of Research on Adolescent Risk and Psychopathology

Drawing on a conception of scientists and community members as partners in the construction of ethically responsible research practices, this article urges investigators to seek the perspectives of teenagers and parents in evaluating the personal and political costs and benefits of research on adolescent risk behaviors. Content analysis of focus group discussions involving over 100 parents and teenagers from diverse ethnic and socioeconomic backgrounds revealed community opinions regarding the scientific merit, social value, racial bias, and participant and group harms and benefits associated with surveys, informant reports, intervention studies, blood sampling, and genetic research on youth problems. Participant comments highlight new directions for socially responsible research.