Selecting participants fairly for controlled human infection studies

Controlled human infection (CHI) studies involve the deliberate exposure of healthy research participants to infectious agents to study early disease processes and evaluate interventions under controlled conditions with high efficiency. Although CHI studies expose participants to the risk of infection, they are designed to offer investigators unique advantages for studying the pathogenesis of infectious diseases and testing potential vaccines or treatments in humans. One of the central challenges facing investigators involves the fair selection of research subjects to participate in CHI studies. While there is widespread agreement that investigators have a duty to select research participants fairly, this principle also yields conflicting ethical imperatives, for example requiring investigators to both exclude potential participants with co-morbidities since they face increased risks, but also to include them in order to ensure generalizability. In this paper we defend an account of fair subject selection that is tailored to the context of CHI studies. We identify the considerations of fairness that bear directly on selecting participants for CHI studies and provide investigators and members of IRBs and RECs with a principled way to navigate the conflicting imperatives to which these considerations give rise.     

Judging the social value of controlled human infection studies

In controlled human infection (CHI) studies, investigators deliberately infect healthy individuals with pathogens in order to study mechanisms of disease or obtain preliminary efficacy data on investigational vaccines and medicines. CHI studies offer a fast and cost-effective way of generating new scientific insights, prioritizing investigational products for clinical testing, and reducing the risk that large numbers of people are exposed to ineffective or harmful substances in research or in practice. Yet depending on the pathogen, CHI studies can involve significant risks or burdens for participants, pose risks to individuals or communities not involved in the research, and lead to public controversy. It is therefore essential to ensure that the risks of CHI studies are justified by their social value—that is, their potential to generate benefits for society—and that public trust can be maintained. In this paper, we aim to clarify how research sponsors, research ethics committees and other reviewers should judge the social value of CHI studies. We develop a list of relevant considerations for making social value judgments based on the standard view of social value. We then use this list to discuss the example of potentially conducting dengue virus CHI studies in endemic settings. We argue that dengue virus CHI studies in endemic settings would fall on the higher end of the spectrum of social value, mostly because of their potential to redirect all fields of future dengue research. Drawing on this discussion, we derive several general recommendations for how reviewers should judge the social value of CHI studies.     

Informed consent for controlled human infection studies in low- and middle-income countries: Ethical challenges and proposed solutions

In controlled human infection studies (CHIs), participants are deliberately exposed to infectious agents in order to better understand the mechanism of infection or disease and test therapies or vaccines. While most CHIs have been conducted in high-income countries, CHIs have recently been expanding into low- and middle-income countries (LMICs). One potential ethical concern about this expansion is the challenge of obtaining the voluntary informed consent of participants, especially those who may not be literate or have limited education. In some CHIs in LMICs, researchers have attempted to address this potential concern by limiting access to literate or educated populations. In this paper, we argue that this practice is unjustified, as it does not increase the chances of obtaining valid informed consent and therefore unfairly excludes illiterate populations and populations with lower education. Instead, we recommend that investigators improve the informed consent process by drawing on existing data on obtaining informed consent in these populations and interventions aimed at improving their understanding. Based on a literature review, we provide concrete suggestions for how to follow this recommendation and ensure that populations with lower literacy or education are given a fair opportunity to protect their rights and interests in the informed consent process.     

Decision analysis approach to risk/benefit evaluation in the ethical review of controlled human infection studies

Risks and benefit evaluation for controlled human infection studies, where healthy volunteers are deliberately exposed to infectious agents to evaluate vaccine efficacy, should be explicit, systematic, thorough, and non-arbitrary. Decision analysis promotes these qualities using four steps: (1) determining explicit criteria and measures for evaluation, (2) identifying alternatives to the study, (3) defining the models used to estimate the measures for each alternative, and (4) running the models to produce the estimates and compare the alternatives. In this paper, we describe how decision analysis might be applied by funders and regulators, as well as by others contemplating the use of novel controlled human infection studies for vaccine development and evaluation.     

Deliberately infecting healthy volunteers with malaria parasites: Perceptions and experiences of participants and other stakeholders in a Kenyan-based malaria infection study

Controlled human malaria infection (CHMI) studies involve the deliberate infection of healthy volunteers with malaria parasites under controlled conditions to study immune responses and/or test drug or vaccine efficacy. An empirical ethics study was embedded in a CHMI study at a Kenyan research programme to explore stakeholders’ perceptions and experiences of deliberate infection and moral implications of these. Data for this qualitative study were collected through focus group discussions, in-depth interviews and non-participant observation. Sixty-nine participants were involved, including CHMI study volunteers, community representatives and research staff. Data were managed using QSR Nvivo 10 and analysed using an inductive-deductive approach, guided by ethics literature. CHMI volunteers had reasonable understanding of the study procedures. Decisions to join were influenced by study incentives, trust in the research institution, their assessment of associated burdens and motivation to support malaria vaccine development. However, deliberate malaria infection was a highly unusual research strategy for volunteers, community representatives and some study staff. Volunteers’ experiences of physical, emotional and social burdens or harms were often greater than anticipated initially, and fluctuated over time, related to specific procedures and events. Although unlikely to deter volunteers' participation in similar studies in furture, we argue that the dissonance between level of understanding of the burdens involved and actual experiences are morally relevant in relation to community engagement, informed consent processes, and ongoing support for volunteers and research staff. We further argue that ethics oversight of CHMI studies should take account of these issues in deciding whether consent, engagement and the balance of benefits and harms are reasonable in a given context.     

The Ethical Conduct of Studies Involving Controlled Human Exposure to Environmental Pollutants

In recent years, the concern for human research subject protection has increased markedly in the United States. The nature of research subject participation in controlled-exposure environmental health research is such that the individual subject bears the risk of participation, while the benefits of such research accrue to society. Therefore, particular attention must be paid when designing studies to protect the health and safety of human research subject. This paper outlines principles for the appropriate selection of pollutants to which humans can be exposed, and the principles that should be used to protect the health and safety of human research subject.     

The right to withdraw from controlled human infection studies: Justifications and avoidance

The right to withdraw from research without penalty is well established around the world. However, it has been challenged in some corners of bioethics based on concerns about various harms—to participants, to scientific integrity, and to research bystanders—that may stem from withdrawal. These concerns have become particularly salient in emerging debates about the ethics of controlled human infection (CHI) studies in which participants are intentionally infected with pathogens, often in inpatient settings with extensive follow-up. In this article, I provide support for preserving the right to withdraw from research without penalty and demonstrate that it is also typically justified in the specific context of CHI studies. The right is well aligned with individual freedoms outside the research setting, where autonomous individuals are permitted to engage in behaviors that will foreseeably cause them harm; where they cannot be compelled to satisfy contracts for their services, nor penalized for failure to do so; and where their behavior is not constrained by public health authorities except in extreme circumstances. These freedoms are supported by U.S. law, as well as by ethical analysis that is more globally relevant. The problems associated with the right to withdraw, however, remain. The best approach to addressing them is not to restrict the right but rather to avoid initiating research when withdrawal would be especially problematic. If research proceeds, steps can still be taken to minimize participant withdrawal without infringing the right. Investigators can avoid participant surprise through informed consent focused on a study’s most burdensome aspects and promote study completion through financial incentives. Should participants nonetheless seek to withdraw, investigators may attempt to persuade them not to do so by encouraging consideration of the range of potential harms that may result. Researchers conducting CHI studies and other research from which withdrawal might be especially problematic should prepare for the possibility of participant withdrawal, respect participant requests to withdraw without penalty, and incorporate various measures to avoid such requests.     

The role of community engagement in addressing bystander risks in research: The case of a Zika virus controlled human infection study

There is limited guidance on how to assess the ethical acceptability of research risks that extend beyond research participants to third parties (or “research bystanders”). Community or stakeholder engagement has been proposed as one way to address potential harms to community members, including bystanders. Despite widespread agreement on the importance of community engagement in biomedical research, this umbrella term includes many different goals and approaches, agreement on which is ethically required or recommended for a particular context. We analyse the case of a potential Zika virus human challenge trial to assess whether and how community engagement can help promote the ethical acceptability of research posing risks to bystanders. We conclude that, in addition to having intrinsic value, community engagement can improve the identification of bystander risks, effective approaches to minimizing them, and transparency about bystander risks for host communities.     

What risks should be permissible in controlled human infection model studies?

Controlled human infection model (CHIM) studies involve the intentional exposure of healthy research volunteers to infectious agents. These studies contribute to knowledge about the cause or development of disease and to the advancement of vaccine research. But they also raise ethical questions about the kinds of risks that should be permissible and whether limits should be imposed on research risks in CHIM studies. Two possible risk thresholds have been considered for CHIM studies. The first suggests constraining ethically permissible risks according to a minimal risk threshold and the second endorses a higher risk threshold that excludes irreversible or fatal infections. I argue that neither of these thresholds is persuasive and situate questions about risk thresholds in CHIM studies within a broader debate about permissible risks in research. I argue that risks in CHIM studies should be constrained according to limits on research risks that do not offer corresponding benefits in all studies rather than developing a unique risk threshold for CHIM studies. I then propose five recommendations for the ethical assessment of risk in CHIM studies.     

Reexamining the categorical exclusion of pediatric participants from controlled human infection trials

Controlled human infection (CHI) models have been developed for numerous pathogens in order to better understand disease processes and accelerate drug and vaccine testing. In the past, some researchers conducted highly controversial CHIs with vulnerable populations, including children. Ethical frameworks for CHIs now recommend vulnerable populations be excluded because they cannot consent to high risk research. In this paper we argue that CHI studies span a wide spectrum of benefit and risk, and that some CHI studies may involve minimal risk. The categorical exclusion of children from CHIs therefore departs from the standard approach to evaluating research risks, as international regulations and ethical guidance for pediatric research generally permit non-beneficial research with low risks. The paradigm in research ethics has also shifted from focusing on protecting vulnerable participants to recognizing that inclusion can be important as a matter of justice, providing new reasons to question this default exclusion of children from CHIs. Recognizing that pediatric CHIs can raise complex ethical issues and are easy to sensationalize in ways that may threaten the public’s trust in research and sponsor institutions, we conclude by describing additional complexities that must be addressed before pediatric CHIs beyond licensed vaccine studies might be ethically acceptable.     

Ethical Concerns Over Testing on Human Subjects

A Joint Subcommittee of the Scientific Advisory Board and the FIFRA Scientific Advisory Panel recently issued a report to the U.S. Environmental Protection Agency (USEPA) concerning the use of data derived from testing on human subjects. The authors address both scientific and ethical issues pertaining to such research and conclude that as long as certain conditions are met, the deliberate exposure of voluntary subjects to potentially dangerous levels of pesticides can be both scientifically and ethically sound. I argue that there are further ethical problems not adequately addressed in the report. In particular, there are serious concerns about fairness and exploitation in connection with paid volunteers, which also raise questions about the degree to which the conditions of non-coercion and informed consent are likely to be met. The primary aim of this paper is to bring these issues more fully into the discussion. I also consider briefly the constraints placed on legitimate justifications of human studies by the requirement that the promotion of public safety be the ultimate purpose of the studies. This will help to clarify which reasons in support of human studies are in principle legitimate, which will in turn better enable us to weigh them against the ethical concerns about fairness and exploitation.     

Ethical issues associated with HIV phylogenetics in HIV transmission dynamics research: A review of the literature using the Emanuel Framework

The reduced costs of DNA sequencing and the use of such data for HIV‐1 clinical management and phylogenetic analysis have led to a massive increase of HIV‐1 sequences in the last few years. Phylogenetic analysis has shed light on the origin, spread and characteristics of HIV‐1 epidemics and outbreaks. Phylogenetic analysis is now also being used to advance our knowledge of the drivers of HIV‐1 transmission in order to design effective interventions. However, HIV phylogenetic analysis presents unique ethical challenges, which have not been fully explored. This review presents an analysis of what appear to be key ethical issues in HIV phylogenetics in the hope of stimulating further conceptual and empirical work in this rapidly emerging area. We structure the review using the Emanuel Framework, a systematic, holistic framework, which has been adapted for use in developing countries, which bear the brunt of the HIV‐1 pandemic.     

Ethics of human genetic studies in sub-saharan Africa: the case of Cameroon through a bibliometric analysis

Many ethical concerns surrounding human genetics studies remain unresolved. We report here the situation in Cameroon. Objectives: To describe the profile of human genetic studies that used Cameroonian DNA samples, with specific focus on i) the research centres that were involved, ii) authorship, iii) population studied, iv) research topics and v) ethics disclosure, with the aim of raising ethical issues that emerged from these studies. Method: Bibliometric Studies; we conducted a PubMed-based systematic review of all the studies on human genetics that used Cameroonian DNA samples from 1989 to 2009. Results and Discussion: Fifty articles were identified, involving predominantly research centres from Europe (64%) and America (32%). Only 7 (14%) Cameroonian institutions and 14 (28%) Cameroonian authors were associated with these publications. At least 52% of publications were devoted to population genetics (variation/migration patterns) amongst 30 Cameroonian ethnic groups. Very few studies concerned public health related genetic issues and only 5 (10%) references were found for hemoglobinopathies like sickle cell anaemia. Almost all DNA samples are 'banked' outside of the African continent. Capacity building, rights to the genetic information and benefits to the individuals, communities and populations who contribute to these studies are addressed. Conclusions: 1) Our data suggests the need for a wider debate towards building capacity and addressing ethical issues related to human genomic research in sub-Saharan Africa and specifically in Cameroon; 2) National ethical guidelines and regulations concerning the collection, use and storage of human DNA are urgently needed in Cameroon.