Two experiments were run to demonstrate the presence of a partial reinforcement extinction effect (PREE) and a partial punishment effect (PPE) 4 weeks after training in a 1-trial/day procedure. In the PREE paradigm, two groups of animals were trained to run a straight alley for food reward; one group was rewarded on every trial (CRF), whereas the other was rewarded on only 50% of the trials (PRF). In the test phase, extinction, no reward was present on any trial. Four (...) weeks after the end of acquisition, and subsequent to 7 days of CRF retraining, PRF animals showed greater resistance to extinction than did their CRF controls. The PPE paradigm resembled the PREE paradigm in all aspects, except that mild electric foot shock, together with the food reward, was used instead of nonreward on 50% of the acquisition trials. In the test phase, all animals were shocked and given a food reward on every trial. Four weeks after the end of acquisition and retraining, the animals with previous experience of shock in acquisition showed greater resistance to punishment than did their controls. (shrink)

Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose (...) a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs. (shrink)

Research Ethics Committees (RECs) play a critical gatekeeping role in clinical trials. This role is meant to ensure that only those trials that meet certain ethical thresholds proceed through their gate. Two of these thresholds are that the potential benefits of trials are reasonable in relation to risks and that trials are capable of producing a requisite amount of social value. While one ought not expect perfect execution by RECs of their gatekeeping role, one should expect (...) routine success in it. This article reviews a range of evidence showing that substantial numbers of ethically tainted trials are receiving REC approvals. Many of the trials are early phase trials that evidence shows have benefits that may not be reasonable compared with their risks and many others are later trials that evidence shows may lack sufficient social value. The evidence pertains to such matters as methodologically inadequate preclinical studies incapable of supporting the inferences that REC members must make about the prospects for potential benefit needed to offset the risks in early phase trials and sponsorship bias that can cause improperly designed, conducted, analysed and reported later phase trials. The analysis of the evidence makes clear that REC practices need to be strengthened if they are to adequately fulfil their gatekeeping role. The article also explores options that RECs could use in order to improve their gatekeeping function. (shrink)

Recent debates over the use of sham surgery as a control for studies of fetal tissue transplantation for Parkinson’s disease have focused primarily on rival interpretations of the US federal regulations governing human-subjects research. Using the core ethical and methodological considerations that underwrite the equipoise requirement, we nd strong prima facie reasons against using sham surgery as a control in studies of cellular-based therapies for Parkinson’s disease and more broadly in clinical research. Additionally, we believe that these reasons can be (...) generalized to apply to the use of other placebo controls that carry signi cant risks of positive harms in and of themselves. As a result, our arguments are centrally relevant to the emerging drive to subject therapies with a surgical component to the same rigorous standards of evaluation as those governing the approval of new pharmaceuticals. (shrink)

This paper discusses the so-called non-interference assumption (NIA) grounding causal inference in trials in both medicine and the social sciences. It states that for each participant in the experiment, the value of the potential outcome depends only upon whether she or he gets the treatment. Drawing on methodological discussion in clinical trials and laboratory experiments in economics, I defend the necessity of partial forms of blinding as a warrant of the NIA, to control the participants’ expectations and their (...) strategic interactions with the experimenter. (shrink)

This paper focuses on invasive therapeutic procedures, defined as procedures requiring the introduction of hands, instruments, or devices into the body via incisions or punctures of the skin or mucous membranes performed with the intent of changing the natural history of a human disease or condition for the better. Ethical and methodological concerns have been expressed about studies designed to evaluate the effects of invasive therapeutic procedures. Can such studies meet the same standards demanded of those, for example, evaluating pharmaceutical (...) agents? This paper describes a research project aimed at examining the interplay and sometimes apparent conflict between ethical standards for human research and standards for methodological rigor in trials of invasive procedures. The paper discusses how the authors plan to develop a set of consensus standards that, if met, would result in substantial and much-needed improvements in the methodological and ethical quality of such trials. (shrink)

Pragmatic clinical trials (PCTs) seek to show the effectiveness of treatments in routine, clinical practice (MacPherson 2004). However, a number of ethical challenges come to the fore when collater...

It is sometimes thought that randomized study group allocation is uniquely proficient at producing comparison groups that are evenly balanced for all confounding causes. Philosophers have argued that in real randomized controlled trials this balance assumption typically fails. But is the balance assumption an important ideal? I run a thought experiment, the CONFOUND study, to answer this question. I then suggest a new account of causal inference in ideal and real comparative group studies that helps clarify the roles of (...) confounding variables and randomization. 1Confounders and Causes2The Balance Assumption3The CONFOUND Study 3.1CONFOUND 13.2CONFOUND 24Disjunction C and the Ideal Study 4.1The ultimate ‘other cause’: C4.2The ideal comparative group study4.3Required conditions for causal inference5Confounders as Causes, Confounders as Correlates6Summary. (shrink)

Randomised clinical trials provide the most valid means of establishing the efficacy of clinical therapeutics. Ethical standards dictate that patients and clinicians should not consent to randomisation unless there is uncertainty about whether any of the treatment options is superior to the others ("equipoise"). However, true equipoise is rarely present; most randomised trials, therefore, present challenging ethical dilemmas. Minimising the tension between science and ethics is an obligation of investigators and clinicians. This article briefly reviews several techniques for (...) addressing this issue and suggests that unbalanced randomisation, a technique rarely employed in current clinical trial practice, may be useful for enhancing the ethical design of human experimentation. (shrink)

Background and objectives: There are few insights from sub-Saharan Africa on research participants’ experiences of the informed consent process, particularly in the context of randomised controlled trials, where issues of randomisation and the use of placebos may be confusing concepts for participants. This study investigated the knowledge and perceptions of the informed consent process among individuals participating in influenza vaccine trials in two disadvantaged communities in South Africa.Method: Four to 12 months after completion of the trials, participants (...) were contacted to return to participate in the informed consent study. The semistructured questionnaire administered to assess recall of trial procedures and the informed consent process covered key issues including: purpose of the study; awareness that the study was not part of routine treatment; voluntary nature of participation and freedom to withdraw; randomisation; placebos; and remuneration.Results: A total of 334 participants completed the questionnaire. Only 21% were able to recall that they were allocated randomly to the different treatment arms. Only 19% of those involved in the placebo controlled study had interpreted the concept of placebo as an inactive medication.Conclusion: Although a good general recall of trial concepts was demonstrated, only a small proportion of the participants correctly interpreted and recalled the concepts of randomisation and placebos. Informed consent in this and similarly disadvantaged communities may often be inadequate and new ways to improve understanding of the research process should be explored. (shrink)

Phase I clinical trials are the first stage of testing new pharmaceuticals in humans. The majority of these studies are conducted under controlled, inpatient conditions using healthy volunteers who are paid for their participation. This article draws on an ethnographic study of six phase I clinics in the United States, including 268 semistructured interviews with research staff and healthy volunteers. In it, I argue that an institutional banalization of risk structures the perceptions of research staff and healthy volunteers participating (...) in the studies. For research staff, there are three mechanisms by which risk becomes banal: a perceived homogeneity of studies, Fordist work regimes, and data-centric discourse. For healthy volunteers, repeat study participation contributes to the institutional banalization of risk both through the process of desensitization to risk and the formation of trust in the clinics. I argue that the institutional banalization of risk also renders invisible ethical concerns about exploitation of underprivileged groups in pharmaceutical research. (shrink)

Family members can provide crucial support to individuals participating in clinical trials. In research on the “newest frontier” of Deep Brain Stimulation (DBS)—the use of DBS for psychiatric conditions—family member support is frequently listed as a criterion for trial enrollment. Despite the significance of family members, qualitative ethics research on DBS for psychiatric conditions has focused almost exclusively on the perspectives and experiences of DBS recipients. This qualitative study is one of the first to include both DBS recipients and (...) their family members as interview participants. Using dyadic thematic analysis—an approach that takes both the individuals and the relationship as units of analyses—this study analyzes the complex ways in which family relationships can affect DBS trial participation, and how DBS trial participation in turn influences family relationships. Based on these findings, we propose ways to improve study designs to better take family relationships into account, and better support family members in taking on the complex, essential roles that they play in DBS trials for psychiatric conditions. (shrink)

Much has changed in maternal-fetal medicine since the early 2000s, when the previous ethical frameworks for fetal therapy trials were established. We applaud Hendriks and colleagues for taking on t...

Randomised controlled trials (RCTs) sometimes recruit participants who are desperate to receive the experimental treatment. This paper defends the practice against three arguements that suggest it is unethical first, desperate volunteers are not in equipoise. Second clinicians, entering patients onto trials are disavowing their therapeutic obligation to deliver the best treatment; they are following trial protocols rather than delivering individualised care. Research is not treatment; its ethical justification is different. Consent is crucial. Third, desperate volunteers do not give (...) proper consent: effectively, they are coerced. This paper responds by advocating a notion of equipoise based on expert knowledge and widely shared values. Where such collective, expert equipoise exists there is a prima facie case for an RCT. Next the paper argues that trial entry does not involve clinicians disavowing their therapeutic obligation; individualised care based on insufficient evidence is not in patients best interest. Finally, it argues that where equipoise exists it is acceptable to limit access to experimental agents; desperate volunteers are not coerced because their desperation does not translate into a right to receive what they desire. (shrink)

Vaccines are a powerful measure to protect the health of individuals and to combat outbreaks such as the COVID-19 pandemic. An ethical dilemma arises when one effective vaccine has been successfully developed against an epidemic disease and researchers seek to test the efficacy of another vaccine for the same pathogen in clinical trials involving human subjects. On the one hand, there are compelling reasons why it would be unethical to trial a novel vaccine when an effective product exists already. (...) First, it is a firm principle of medical ethics that an effective treatment or vaccine should not be withheld from patients if their life may depend on it. Second, since epidemic outbreaks often emerge in settings with less-resourced health systems, there is a pronounced risk that any trial withholding an effective vaccine would disproportionately affect the vulnerable populations that historically have been exploited for biomedical research. Third, clinical trials for novel vaccines may be at odds with efforts to control active outbreaks. On the other hand, it may be justified to conduct a trial for a candidate vaccine if it is expected to have certain advantages compared with the existing product. This essay discusses key factors for comparing vaccines against epidemic pathogens, including immunological, logistical and economic considerations. Alongside a case study of the development of vaccines for Ebola, the essay seeks to establish a general framework that should be expanded and populated by immunologists, epidemiologists, economists and bioethicists, and ultimately could be applied to the case of COVID-19 vaccines. (shrink)

In 2008 UK legislation was amended to enable the use of deferred consent for paediatric emergency care (EC) trials in recognition of the practical and ethical difficulties of obtaining prospective consent in an emergency situation. However, ambiguity about how to make deferred consent acceptable to parents, children and practitioners remains. In particular, little is known about practitioners’ views and experiences of seeking deferred consent in this setting.

The paper investigates how field experimentation of genetically modified crops became central to the French controversy on genetically modified organisms in recent years. Initially constructed in the 1980s as a cognitive endeavor to be preserved from lay interference, field trials of genetically modified crops were reconceived as “an intrusion in the social space,” which had to be negotiated with actors from that space. In order to analyze this transformation, the authors suggest that it is necessary to develop an interpretive (...) framework that combines theoretical perspectives from science and technology studies and the sociology of social problems, and emphasizes the importance of the way in which actors compete in a heterogeneous public space, to put forward alternative framings of problems. The authors present a detailed analysis of the interactions and conflicts between actors in diverse social arenas in order to better understand the dynamics of this sociotechnical controversy. (shrink)

Unregulated patient treatments and approved clinical trials have been conducted with haematopoietic stem cells and mesenchymal stem cells for children with autism spectrum disorder. While the former direct-to-consumer practice is usually considered rogue and should be legally constrained, regulated clinical trials could also be ethically questionable. Here, we outline principal objections against these trials as they are currently conducted. Notably, these often lack a clear rationale for how transplanted cells may confer a therapeutic benefit in ASD, and (...) thus, have ill-defined therapeutic outcomes. We posit that ambiguous and unsubstantiated descriptions of outcome from such clinical trials may nonetheless appeal to the lay public as being based on authentic scientific findings. These may further fuel caregivers of patients with ASD to pursue unregulated direct-to-consumer treatments, thus exposing them to unnecessary risks. There is, therefore, a moral obligation on the part of those regulating and conducting clinical trials of stem cell-based therapeutic for ASD minors to incorporate clear therapeutic targets, scientific rigour and reporting accuracy in their work. Any further stem cell-based trials for ASD unsupported by significant preclinical advances and particularly sound scientific hypothesis and aims would be ethically indefensible. (shrink)

Human subject trials of pharmaceuticals in low and middle income countries have been associated with the moral wrong of exploitation on two grounds. First, these trials may include a placebo control arm even when proven treatments for a condition are in use in other parts of the world. Second, the trial researchers or sponsors may fail to make a successful treatment developed through the trial available to either the trial participants or the host community following the trial.Many commentators (...) have argued that a single form of exploitation takes place during human subject research in LMICs. These commentators do not, however, agree as to what kind of moral wrong exploitation is or when exploitation is morally impermissible. In this paper, I have two primary goals. First, I will argue for a taxonomy of exploitation that identifies three distinct forms of exploitation. While each of these forms of exploitation has its critics, I will argue that they can each be developed into plausible accounts of exploitation tied to different vulnerabilities and different forms of wrongdoing. Second, I will argue that each of these forms of exploitation can coexist in single situations, including human subject trials of pharmaceuticals. This lesson is important, since different forms of exploitation in a single relationship can influence, among other things, whether the relationship is morally permissible. (shrink)

Well-designed pragmatic clinical trials (PCTs) are critical for improving healthcare delivery and patient outcomes (Haff and Choudhry 2018), and the article written by Garland et al. (2023) advance...

In recent years much research has been undertaken regarding the feasibility of the human uterine transplant as a treatment for absolute uterine factor infertility. Should it reach clinical application this procedure would allow such individuals what is often a much-desired opportunity to become not only social mothers, or genetic and social mothers but mothers in a social, genetic and gestational sense. Like many experimental transplantation procedures such as face, hand, corneal and larynx transplants, UTx as a therapeutic option falls firmly (...) into the camp of the quality of life transplant, undertaken with the aim, not to save a life, but to enrich one. However, unlike most of these novel procedures – where one would be unlikely to find a willing living donor or an ethics committee that would sanction such a donation – the organs to be transplanted in UTx are potentially available from both living and deceased donors. In this article, in the light of the recent nine-case research trial in Sweden which used uteri obtained from living donors, and the assertions on the part of a number of other research teams currently preparing trials that they will only be using deceased donors, I explore the question of whether, in the case of UTx, there exist compelling moral reasons to prefer the use of deceased donors despite the benefits that may be associated with the use of organs obtained from the living. (shrink)

Ongoing and anticipated COVID-19 human challenge studies in the UK may advance our understanding of COVID-19 and facilitate the licensure of safe, effective, and easily deployable next-generation COVID-19 vaccines and boosters. We argue that international volunteer recruitment for COVID-19 human challenge trials can help promote diversity in these trials and ensure a sufficient number of eligible volunteers, both of which will increase the benefits of challenge research. We explore the ethical ramifications of dealing with unfair background conditions of (...) global vaccine injustice to expand medical research, and conclude that international recruitment for COVID-19 human challenge trials can be conducted ethically provided that several robust protections are in place for volunteers. (shrink)

One way to test vaccines is through human challenge trials in which participants are intentionally infected with a contagious organism to expedite the process of assessing the vaccine’s effectiveness. Some experts believe challenge trials may play an important role in fighting COVID-19, especially if the vaccines under current study do not demonstrate sufficient efficacy, if spread of COVID-19 is controlled to a point that radically slows down traditional trials, or if new vaccines need to be rapidly developed (...) for specific subpopulations.1 Challenge trials involve significant time, burden and risk, requiring participants to spend 3–6 weeks in legal quarantine for 24 hours a day in a high-security facility. During this time, no inperson visitors will be allowed, except for very limited inperson contact from researchers collecting necessary data and checks. Following the quarantine period, participants will be asked to attend numerous outpatient follow-up visits over the course of months, to further monitor their response to the vaccine. Participation involves being away from family who may themselves become sick during the global pandemic, as well as potential fear and mental anguish around being a ‘first’ subject. Because there is no definitive treatment for COVID-19, participants could experience serious illness. But even with milder illness, medical experts know very little about the long-term consequences of COVID-19 infection. This raises the question of how much people should be paid for their participation in COVID-19 challenge trials. Most think participants should be paid something, but many contend that we should be …. (shrink)

Effective community engagement is an important legal, ethical, and practical prerequisite for conducting field trials of genetically modified mosquitoes, because these studies can substantially impact communities and it is usually not possible to obtain informed consent from each community member. Researchers who are planning to conduct field trials should develop a robust community engagement strategy that meets widely recognized standards for seeking approval from the affected population, such as timeliness, consent, information sharing, transparency, understanding, responsiveness, mutual understanding, inclusiveness, (...) and respectfulness. Additional research is needed on the effectiveness of different methods of engaging communities in field trials of genetically modified mosquitoes and how to respond to public opposition to genetically modified organisms. For research programs involving the genetic modification of disease vectors to move forward, they must have public acceptance and support, which cannot be achieved without effective community engagement. (shrink)