Against the inalienable right to withdraw from research

In this paper I argue, against the current consensus, that the right to withdraw from research is sometimes alienable. In other words, research subjects are sometimes morally permitted to waive their right to withdraw. The argument proceeds in three major steps. In the first step, I argue that rights typically should be presumed alienable, both because that is not illegitimately coercive and because the general paternalistic motivation for keeping them inalienable is untenable. In the second step of the argument, I consider three special characteristics of the right to withdraw, first that its waiver might be exploitative, second that research involves intimate bodily access, and third that it is irreversible. I argue that none of these characteristics justify an inalienable right to withdraw. In the third step, I examine four considerations often taken to justify various other allegedly inalienable rights: concerns about treating yourself merely as a means as might be the case in suicide, concerns about revoking all your future freedoms in slavery contracts, the resolution of coordination problems, and public interest. I argue that the motivations involved in these four types of situations do not apply to the right to withdraw from research.     

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.     

Research participation and the right to withdraw

Most ethics committees which review research protocols insist that potential research participants reserve unconditional or absolute 'right' of withdrawal at any time and without giving any reason. In this paper, I examine what consent means for research participation and a sense of commitment in relation to this right to withdraw. I suggest that, once consent has been given (and here I am excluding incompetent minors and adults), participants should not necessarily have unconditional or absolute rights to withdraw. This does not imply that there should be a complete absence of rights, or, indeed, an abandonment of the right to withdraw. The point of this paper is to show that the supposed unconditional or absolute nature of these rights may be self-defeating and so fail to respect the autonomy of participants. In addition, and on a more positive note, I suggest that, attaching certain conditions on the right to withdraw, may better respect the autonomy of these participants by underlining the idea that autonomy is more than mere whim or indifference to the fate of others. On the contrary, research staff are currently unable to 'push' participants, who may merely have logistical difficulties unrelated to the research itself, but who really want to stay the course, for fear of coercing them. Furthermore, researchers now try to 'screen out' people they think may be unreliable to protect the science of the study and so groups at risk of dropping out may be unfairly denied access to research treatments. I conclude that on-going negotiation between the relevant parties could be on balance the only truly acceptable way forward but concede certain important limitations to take into account.     

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.     

STAKEHOLDER PERSPECTIVES ON ETHICAL CHALLENGES IN HIV VACCINE TRIALS IN SOUTH AFRICA

There is little published literature on the ethical concerns of stakeholders in HIV vaccine trials. This study explored the ethical challenges identified by various stakeholders, through an open-ended, in-depth approach. While the few previous studies have been largely quantitative, respondents in this study had the opportunity to spontaneously identify the issues that they perceived to be of priority concern in the South African context. Stakeholders spontaneously identified the following as ethical priorities: informed consent, social harms, collaborative relationships between research stakeholders, the participation of children and adolescents, access to treatment for participants who become infected with HIV, physical harms, fair participant and community selection, confidentiality, benefits, and payment.
While there is some speculation that research in developing countries poses special ethical challenges, overall no issues were identified that have not been anticipated in international guidance, literature and popular frameworks. However, the South African context affords a distinctive gloss to these expected issues; for example, respondents were concerned that the predominant selection of black participants may perpetuate racist practices of apartheid. Stakeholders should be aware of contextual factors impacting on the implementation of ethical principles. We make a series of recommendations for South African trials, including amendments to the ethical-legal framework and research policies, and, for further research.     

Medicine’s collision with false hope: The False Hope Harms (FHH) argument

The goal of this paper is to introduce the false hope harms (FHH) argument, as a new concept in healthcare. The FHH argument embodies a conglomerate of specific harms that have not convinced providers to stop endorsing false hope. In this paper, it is submitted that the healthcare profession has an obligation to avoid collaborating or participating in, propagating or augmenting false hope in medicine. Although hope serves important functions—it can be ‘therapeutic’ and important for patients’ ‘self-identity as active agents’— the presentation of false hope along the hope continuum entails a misconstrued balancing act. By not speaking up against unrealistic patient and family requests—including some requests for rights to try, resuscitative efforts in terminally ill patients, or other demands for non-beneficial treatments—healthcare providers precipitate harms, i.e., the FHH. These harms arise on both individual and communal levels and cannot be ignored. The goal of this paper is not to offer a definition of false hope, because the phenomenon of false hope is too complex for any simple definition. Instead, this paper seeks to make four points while outlining the FHH argument: consumer medicine and false hope are connected; providers and patients are very vulnerable in the system of consumer medicine; providers have a responsibility to stand up against false hope; and how the FHH argument could perhaps offer a footing to resist giving in to false hope.     

“The One Who Chases You Away Does Not Tell You Go”: Silent Refusals and Complex Power Relations in Research Consent Processes in Coastal Kenya

Consent processes have attracted significant research attention over the last decade, including in the global south. Although relevant studies suggest consent is a complex negotiated process involving multiple actors, most guidelines assume consent is a one-off encounter with a clear ‘yes’ or ‘no’ decision. In this paper we explore the concept of ‘silent refusals’, a situation where it is not clear whether potential participants want to join studies or those in studies want to withdraw from research, as they were not actively saying no. We draw on participant observation, in-depth interviews and group discussions conducted with a range of stakeholders in two large community based studies conducted by the KEMRI Wellcome Trust programme in coastal Kenya. We identified three broad inter-related rationales for silent refusals: 1) a strategy to avoid conflicts and safeguard relations within households, - for young women in particular—to appear to conform to the wishes of elders; 2) an approach to maintain friendly, appreciative and reciprocal relationships with fieldworkers, and the broader research programme; and 3) an effort to retain study benefits, either for individuals, whole households or wider communities. That refusals and underlying rationales were silent posed multiple dilemmas for fieldworkers, who are increasingly recognised to play a key interface role between researchers and communities in many settings. Silent refusals reflect and reinforce complex power relations embedded in decisions about research participation, with important implications for consent processes and broader research ethics practice. Fieldworkers need support to reflect upon and respond to the ethically charged environment they work in.     

Participant informed consent in cluster randomized trials: review

Background

The Nuremberg code defines the general ethical framework of medical research with participant consent as its cornerstone. In cluster randomized trials (CRT), obtaining participant informed consent raises logistic and methodologic concerns. First, with randomization of large clusters such as geographical areas, obtaining individual informed consent may be impossible. Second, participants in randomized clusters cannot avoid certain interventions, which implies that participant informed consent refers only to data collection, not administration of an intervention. Third, complete participant information may be a source of selection bias, which then raises methodological concerns. We assessed whether participant informed consent was required in such trials, which type of consent was required, and whether the trial was at risk of selection bias because of the very nature of participant information.

Methods and Findings

We systematically reviewed all reports of CRT published in MEDLINE in 2008 and surveyed corresponding authors regarding the nature of the informed consent and the process of participant inclusion. We identified 173 reports and obtained an answer from 113 authors (65.3%). In total, 23.7% of the reports lacked information on ethics committee approval or participant consent, 53.1% of authors declared that participant consent was for data collection only and 58.5% that the group allocation was not specified for participants. The process of recruitment (chronology of participant recruitment with regard to cluster randomization) was rarely reported, and we estimated that only 56.6% of the trials were free of potential selection bias.

Conclusions

For CRTs, the reporting of ethics committee approval and participant informed consent is less than optimal. Reports should describe whether participants consented for administration of an intervention and/or data collection. Finally, the process of participant recruitment should be fully described (namely, whether participants were informed of the allocation group before being recruited) for a better appraisal of the risk of selection bias.     

Reconsidering paternalism in clinical research

The ethical standards that regulate clinical research have multiple rationales. Among them is the need to protect potential subjects from making imprudent decisions, which extends beyond the soft paternalistic concern to protect people from making uninformed decisions to participate in trials. This article argues that a plausible risk/benefit restriction on clinical trials is presumptively justified by hard paternalism, which in turn is supported by a deeper fairness‐based rationale. This presumptive case for hard paternalism in research is not defeated by the alleged right to participate in clinical trials, by concerns about insult or status, by the need to conduct early phase trials that promise little to no benefit to participants, or by the recognition that some potential subjects are altruistically motivated.     

HARD PATERNALISM,FAIRNESS AND CLINICAL RESEARCH: WHY NOT?

Jansen and Wall suggest a new way of defending hard paternalism in clinical research. They argue that non‐therapeutic research exposing people to more than minimal risk should be banned on egalitarian grounds: in preventing poor decision‐makers from making bad decisions, we will promote equality of welfare. We argue that their proposal is flawed for four reasons. First, the idea of poor decision‐makers is much more problematic than Jansen and Wall allow. Second, pace Jansen and Wall, it may be practicable for regulators to uncover the values that a potential research participant holds when agreeing to enter a research project, so their claim that we must ban such research projects for all if we are to ban them for poor decision‐makers looks to be unmotivated. Third, there seem to be cases where the liberty to enter the sort of research project Jansen and Wall discuss is morally weighty, and arguably should outweigh concerns of egalitarian distribution. Fourth, banning certain types of research, which seem on the face of it to offer an unfavourable risk‐benefit ratio, would have unwelcome consequences for all clinical research, which Jansen and Wall do not recognize.     

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.     

Improving Retention of Very Old Participants in Longitudinal Research: Experiences from the Newcastle 85+ Study

Background

People aged 85 and over are often excluded from research on the grounds of being difficult to recruit and problematic to retain. The Newcastle 85+ study successfully recruited a cohort of 854 85-year-olds to detailed health assessment at baseline and followed them up over 3 phases spanning 5 years. This paper describes the effectiveness of its retention strategies.

Methods

Primary retention strategies involved meticulous management of contact information and active maintenance of contact with participants between research visits and between phases of the study. For statistical analysis, data on post-inclusion attrition over the 3 follow-up phases was separated into ‘death’ and ‘withdrawal’ categories, with sub-categories ‘health’ and ‘non-health’ reasons created for ‘withdrawal’. Multinomial logistic regression was used to determine if particular socio-demographic and health characteristics were associated with post-inclusion attrition due to withdrawal at each of the 3 phase-to-phase transition points.

Results

For both sexes, at successive follow-up phases there was a decrease in attrition due to withdrawal and an increase due to death. Withdrawal was most prevalent between baseline and phase 2. Across the 5 years of the study total post-inclusion (post-baseline) attrition due to death accounted for a 40% (344/854) loss to cohort and total post-inclusion attrition due to withdraw a 19% (166/854) loss to cohort, with health reasons for withdrawal becoming more dominant over time. Adjusting for sex, parsimonious modelling showed only occupational class (National Statistics Socio-economic Classification) to be associated with withdrawal and only between baseline and phase 2 (routine/manual compared to managerial (OR 3.41; 95% CI [1.23 to 9.44]).

Conclusion

Following successful recruitment, we retained a high proportion of participants from a very old age group over 5 years of longitudinal research. No strong predictors of post-inclusion attrition due to withdrawal were found, suggesting the general effectiveness of our retention strategies.     

Ethical issues surrounding controlled human infection challenge studies in endemic low-and middle-income countries

Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro-organisms. There have been increased calls for more CHIs to be conducted in low- and middle-income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third-party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well-designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly.     

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.     

The incompatibility of the United Nations' goals and conventionalist ethical relativism

The Universal Draft Declaration on Bioethics and Human Rights seeks to provide moral direction to nations and their citizens on a series of bioethical concerns. In articulating principles, it ranks respect for human rights, human dignity and fundamental freedoms ahead of respect for cultural diversity and pluralism. This ranking is controversial because it entails the rejection of the popular theory, conventionalist ethical relativism. If consistently defended, this theory also undercuts other United Nations activities that assume member states and people around the world can reach trans-cultural judgments having moral authority about health, pollution, aggression, rights, slavery, and so on. To illustrate problems with conventionalist ethical relativism and the importance of rejecting it for reasons of health, human rights, human dignity and fundamental freedoms, the widespread practice of female genital circumcision or cutting is discussed. These surgeries are virtually a test case for conventionalist ethical relativism since they are widely supported within these cultures as religious and health practices and widely condemned outside them, including by the United Nations.     

The Mid-Atlantic Twin Registry.

The Mid-Atlantic Twin Registry (MATR) is a population-based registry of twin pairs ascertained from birth records and school system records of Virginia, North Carolina, and South Carolina. The MATR was formed in 1997 with the merging of the Virginia and North Carolina Twin Registries, and it expanded to include South Carolina when access to twin birth records in that state was granted in 1998. Registered twins ("participants") number more than 51,000, with approximately 46,000 of these individuals representing complete pairs. Roughly two-thirds of MATR participants are over age 18, with a mean age of approximately 35 years. These participants have primarily been drawn from the more than 170,000 identical and fraternal twin pairs born in the three states between 1913 and 2000. Twins and their family members have participated in numerous research projects, ranging from general health surveys to studies on specific health topics such as cardiovascular disease; depression and anxiety; seizures; behavioral development; pregnancy complications; conduct disorder; drug use, abuse, and dependence; cleft lip/palate; obesity; and chronic fatigue syndrome. The MATR has established a privacy policy and strict standard operating procedures to protect the confidentiality of participant data. The MATR considers a limited number of qualified requests per year from investigators interested in recruiting MATR participants into their research studies.     

NO ETHICAL BYPASS OF MORAL STATUS IN STEM CELL RESEARCH

Recent advances in reprogramming technology do not bypass the ethical challenge of embryo sacrifice. Induced pluripotent stem cell (iPS) research has been and almost certainly will continue to be conducted within the context of embryo sacrifice. If human embryos have moral status as human beings, then participation in iPS research renders one morally complicit in their destruction; if human embryos have moral status as mere precursors of human beings, then advocacy of iPS research policy that is inhibited by embryo sacrifice concerns renders one morally complicit in avoidable harms to persons. Steps may be taken to address these complicity concerns, but in the final analysis there is no alternative to achieving clarity with respect to the moral status of the human embryo.     

Researchers' ethical concerns regarding habituating wild-nonhuman primates and perceived ethical duties to their subjects: Results of an online survey

While the process of habituation is essential for researchers to observe primates in their natural habitats, ethical dilemmas may arise from its consequences. We collected data from 286 participants via an online survey to investigate: (a) how primatologists perceive their ethical duties toward their subjects; (b) the extent to which primatologists are concerned about the potential ethical consequences of habituation; and (c) the methods primatologists use to reduce potential harms caused by habituation. Overall, primatologists felt an extremely strong duty to mitigate harms that they may cause (e.g., to not stress individuals during observation, treat injuries, and reunite separated individuals) and expressed very high concern for habituation's potential to increase the vulnerability of their subjects to poaching and disease transfer. Ratings for those items were so high that they could not be included in subsequent exploratory factor analyses that were designed to reveal constructs underlying respondents’ ratings of their ethical duties and concerns. Factor analysis of ratings of ethical duties revealed that primatologists reported a strong duty to mitigate harms caused by other humans and a lower perceived duty to mitigate naturally occurring harmful events. Factor analysis on ethical concern ratings revealed that respondents were concerned about harms during the habituation process, the presence of unhabituated behavior after habituation had been established, and indirect harms of habituation. Concerns for unhabituated behavior and indirect harms were rated slightly higher than concern for harms during the habituation process. To mitigate potential harms, primatologists primarily reported engaging in strategies to reduce stress in their subjects. Our findings reveal a disconnect between primatologists' ratings of their ethical concerns and their reported mitigation practices that may, in part, stem from gaps in knowledge about the true impacts of habituation. We suggest areas of discussion and research in the field necessary to address those gaps.