The 21st-century translational science campaign could lead to an increase in first-in-human trials. As tests of investigational interventions move from the laboratory to human research, scientists, officials, and review committees should address ongoing concerns about the ethics of FIH trials. In this article, I describe three ethical considerations relevant to all FIH trials: the requirement for adequate preclinical research; study design safeguards; and choice of subject population. I also examine specific ethical considerations relevant to the three subject populations (...) involved in FIH research. I recommend a variety of actions that could increase subject protection and the value of the information generated in FIH trials. (shrink)

Translational science is a 21st century mission. Government officials and industry leaders are making huge investments in an attempt to transform more basic science discoveries into therapeutic applications. Scientists and policymakers express great excitement about the medical advances that could come with the current bench-to-bedside campaign.A key step in translational science is the move from animal and other preclinical studies to initial human testing. Researchers ability to predict human effects is limited, and first-in-human tests present significant uncertainty. (...) Participants in this form of research face risks and can experience serious, even lethal, harm. Well-known incidents involving Jolee Mohr and Jesse Gelsinger, as well as subjects in the 2006 study of the investigational agent TGN1412, show the dangers that can arise in early human research.The bench-to-bedside campaign will need many volunteers to participate in early human testing. Investigators and regulators must not allow the policy enthusiasm for translational science to overshadow the commitment to protect human subjects. Participants in exploratory research are diverse and as a group lack characteristics usually associated with vulnerable populations, such as impaired decisional ability or economic or educational disadvantage. (shrink)

The decision to initiate invasive, first-in-human trials involving Parkinson’s disease presents a vexing ethical challenge. Such studies present significant surgical risks, and high degrees of uncertainty about intervention risks and biological effects. We argue that maintaining a favorable riskbenefit balance in such circumstances requires a higher than usual degree of confidence that protocols will lead to significant direct and/or social benefits. One critical way of promoting such confidence is through the application of stringent evidentiary standards for preclinical studies. We (...) close with a series of recommendations for strengthening the internal and external validity of preclinical studies, reducing their tendency toward optimism and publication biases, and improving the knowledge base used to design and evaluate preclinical studies. (shrink)

The discovery of induced pluripotent stem (iPS) cells in 2006 was heralded as a major breakthrough in stem cell research. Since then, progress in iPS cell technology has paved the way towards clinical application, particularly cell replacement therapy, which has refueled debate on the ethics of stem cell research. However, much of the discourse has focused on questions of moral status and potentiality, overlooking the ethical issues which are introduced by the clinical testing of iPS cell replacement therapy. First-in-human (...) trials, in particular, raise a number of ethical concerns including informed consent, subject recruitment and harm minimisation as well as the inherent uncertainty and risks which are involved in testing medical procedures on humans for the first time. These issues, while a feature of any human research, become more complex in the case of iPS cell therapy, given the seriousness of the potential risks, the unreliability of available animal models, the vulnerability of the target patient group, and the high stakes of such an intensely public area of science. Our paper will present a detailed case study of iPS cell replacement therapy for Parkinson's disease to highlight these broader ethical and epistemological concerns. If we accept that iPS cell technology is fraught with challenges which go far beyond merely refuting the potentiality of the stem cell line, we conclude that iPS cell research should not replace, but proceed alongside embryonic and adult somatic stem cell research to promote cross-fertilisation of knowledge and better clinical outcomes. (shrink)

Recent progress in synthetic biology has enabled the development of novel therapeutic opportunities for the treatment of human disease. In the near future, first-in-human trials will be indicated. FIH trials mark a key milestone in the translation of medical SynBio applications into clinical practice. Fostered by uncertainty of possible adverse events for trial participants, a variety of ethical concerns emerge with regards to SynBio FIH trials, including ‘risk’ minimization. These concerns are associated with any FIH trial, (...) however, due to the novelty of the approach, they become more pronounced for medical applications of emerging technologies like SynBio. To minimize potential harm for trial participants, scholars, guidelines, regulations and policy makers alike suggest using ‘risk assessment’ as evaluation tool for such trials. Conversely, in the context of emTech FIH trials, we believe it to be at least questionable to contextualize uncertainty of potential adverse events as ‘risk’ and apply traditional risk assessment methods. Hence, this issue needs to be discussed to enable alterations of the evaluation process before the translational phase of SynBio applications begins. In this paper, we will take the opportunity to start the debate and highlight how a misunderstanding of the concept of risk, and the possibilities and limitations of risk assessment, respectively, might impair decision-making by the relevant regulatory authorities and research ethics committees, and discuss possible solutions to tackle the issue. (shrink)

Given the past two decades of over 40 failed trials of amyloid-lowering therapies in Alzheimer’s Disease (AD), many of which succeeded in lowering amyloid as designed, we present an ethical argument for emptying the drug pipeline of tests of amyloid-lowering agents so as to end the historical dominance of the amyloid-reducing therapeutic approach in AD.

The aims of this article are to consider (1) whether there are medical and societal differences among diseases regarding which patient groups should be asked to participate in first-in-human (FIH) trials of stem-cell-based therapies; (2) any differences in the light of values generally endorsed by different types of ethical theories, since the question in the title of this article is value laden, and its answer depends on which values one wants to promote and protect, and how they are ranked (...) in importance; (3) whether the answer to that question is disease-specific, or whether it depends on factors common to several diseases. To illustrate these problems, we use Parkinson’s disease (PD) and Huntington’s disease (HD), between which there are important medical and societal differences. Moreover, research on stem-cellbased therapies for these diseases is being translated from research to practice. This approach to the problem can be applied to decision making about similar problems raised by other diseases that exhibit the same types of differences. (shrink)

Regulators rely on clinical trials for drug approval and labeling decisions. Health systems and clinicians rely on the evidence from trials to determine treatment, and patients rely on it to decide which courses of care to undertake. Many of these stakeholders presume that the careful review of individual studies is enough to address the ethical and scientific questions that arise in clinical trials. In what follows, however, we demonstrate that explicit consideration of trial portfolios—series of trials that are interrelated (...) by a common set of objectives—is crucial. the ethical acceptability and evidentiary probity of individual trials can change depending on the characteristics of the portfolios in which they are embedded. Second, how trial portfolios are composed, how well they are coordinated, and how efficiently they use information determines the balance of risks and benefits they present as well as their different prospects for generating socially valuable information; these three factors also raise distinct questions of justice. (shrink)

The reporting of clinical trial data is necessary not only for doctors to determine treatment efficacy, but also to explore new questions without unnecessarily repeating trials, and to protect patients and the public from dangers when data are withheld. This issue is particularly salient in those trials involving invasive neurosurgical interventions, such as deep brain stimulation (DBS), for ‘treatment refractory’ psychiatric disorders. Using the federal database ClinicalTrials.gov, it was discovered that out of the completed or unknown‐status trials related to (...) psychiatric DBS up to November 2018, only two had submitted results to ClinicalTrials.gov. These results suggest that, despite federal requirements to report clinical trial data, reporting on psychiatric DBS trials is problematically minimal. It is argued that a human rights approach to this problem establishes a legal and ethical foundation for the need to report clinical trial results in this area. (shrink)

This paper discusses the need to focus on the dignity of human participants as a legal and ethical basis for providing post-trial access to healthcare. Debate about post-trial benefits has mostly focused on access to products or interventions proven to be effective in clinical trials. However, such access may be modelled on a broad fair benefits framework that emphasises both collateral benefits and interventional products of research, instead of prescribed post-trial access alone. The wording of the (...) current version of the Declaration of Helsinki could in fact be interpreted to broaden the scope to include other collateral benefits by applying such a broad fair benefits framework. We argue that this possibility should be utilised by low and middle income countries’ health research ethics committees in order to ensure that research participants who enrol in clinical trials so as to receive medical care continue to access care after the trial is concluded, as befits their dignity. Although each LMIC has unique concerns, nonetheless there are common challenges based especially on emerging issues, such as post-trial access to healthcare. Accordingly, the South African perspective is used to draw lessons that can benefit other LMICs. (shrink)

The “Universal Declaration of Human Rights” and the “Geneva Declaration” by the World Medical Association, both in 1948, were preceded by the foundation of the United Nations in New York (1945), the World Medical Association in London (1946) and the World Health Organization in Geneva (1948). After the end of World War II the community of nations strove to achieve and sustain their primary goals of peace and security, as well as their basic premise, namely the health of (...) class='Hi'>human beings. All these associations were well aware of the crimes by medicine, in particular by the accused Nazi physicians at the Nuremberg Doctors Trial (1946/47, sentence: August 1947). During the first conference of the World Medical Association (September 1947) issues of medical ethics played a major role: and a new document was drafted concerning the values of the medical profession. After the catastrophe of the War and the criminal activities of scientists, the late 1940s saw increased scrutiny paid to fundamental questions of human rights and medical ethics, which are still highly relevant for today’s medicine and morality. The article focuses on the development of medical ethics and human rights reflected in the statement of important persons, codes and institutions in the field. (shrink)

The world’s first COVID-19 human challenge trial using the D614G strain of SARS-CoV-2 is underway in the United Kingdom. The Wellcome Trust is funding challenge stock preparation of the Beta variant (B.1.351) for a follow-up human challenge trial, and researchers at Imperial College London are considering conducting that trial. However, little has been written thus far about the ethical justifiability of human challenge trials with SARS-CoV-2 variants of concern. While vaccine resistance as such does (...) not increase risks for volunteers in COVID-19 challenge trials, we explore two specific characteristics of some variants that may initially be thought to make such trials unethical and conclude that SARS-CoV-2 variant challenge trials can remain ethical. (shrink)

Madole & Harden argue that the Mendelian reshuffling of genes and genomes is analogous to randomised controlled trials. We are not convinced by their arguments. First, their recipe for meeting the demands on randomised experiments is inherently inconsistent. Second, disequilibrium across chromosomes conflicts with their assumption of statistical independence. Third, the genome-wide association study (GWAS) method has many pitfalls, including low repeatability.

The massive growth in global health research in past decades has posed many challenges for its effective ethical oversight, not least of which is how best to provide effective protection of research participants. The extent of the HIV epidemic in sub-Saharan Africa in particular makes research into prevention technologies for HIV, including HIV vaccine research, a global priority. However, the need for vaccine research must be considered in conjunction with the individual's right to informed consent, which is based on the (...) principle of respect for autonomy. One of the primary human rights violations likely to occur in the context of HIV vaccine research is that potential research participants may not fully understand what participation in research studies entails. People who elect to enrol in HIV vaccine trials are required to understand both the potential negative effects of participation (eg, discrimination) as well as complex scientific concepts such as randomisation and prophylaxis in order to be ethically enrolled. In this study, two vignettes are presented to illustrate two core issues in conducting phase III HIV vaccine trials in low-income countries—namely, (1) from the perspective of participants, the extent to which understanding is a prerequisite for consenting to participate in a trial, and (2) from the perspective of trial investigators, whether it is appropriate to persuade eligible people to enrol in a trial, even though their initial reaction is to decline to participate. These vignettes are used to analyse these issues through the prisms of research ethics and human rights in order to identify helpful synergies. It is argued that the human rights perspective provides a helpful lens on ethical issues. (shrink)

Fragmented social relations, the twin demise of authority and tradition, the breakdown of behavioural norms and constraints: all these are the outcome, according to their critics, of the uses and abuses of human rights in contemporary democratic societies. We are, they say, seeing the perverse effects of a 'religion of human rights' to which Europe has rashly devoted its heart and mind; and the supposed burgeoning of rights, which goes hand in hand with an unchecked rise of expectations, (...) is catapulting Western democracies into an age of never-ending demands. This emerged clearly in France in Spring 2013 during the demonstrations against equal marriage ('mariage pour tous') whose opponents deplored the excesses of a movement-driven left striving for an unbounded extension of rights - from the right to same-sex marriage to the enfranchisement of non-nationals or the right of same-sex couples to adopt. (shrink)

Tremendous development in recent medical science and the consequent discoveries resulting in successful prevention and also cure of different diseases are shared by clinical research involving the human volunteers. Preceding the trials in the human subjects, and to ensure safety, the proposed drug and other interventions are either tested in animals (vivo) or in laboratory (vitro) to evaluate initial safe starting dose for the human beings and to key out the benchmarks for the clinical monitoring for the (...) potential unfavorable effects. These pre human trials might not necessarily protect against the untoward effects in the human beings as happened in the case of thalidomide tragedy, which caused disability and killed thousands of babies born to the mothers, those who took this medicine. Use of healthy human volunteers in the preliminary experiments or phase I clinical trials either reduces or excludes risks of subsequent undesirable effects in the future trails (1). Phase-1 trials are conducted in order to test the safety, reactions and immunogenicity of vaccines in volunteers. Novel treatments for the cancer are first tested in phase 1 trials enrolling the patients with advanced disease, who have exhausted the standard treatment options. Phase-1 oncology trials are the pivot point in the translation of new cancer therapies from bench to bedside. Nevertheless, these trials remain ethically controversial. The controversy stems from the fact that, classically, phase-1 oncology clinical trials involve first-in-human testing of experimental treatment candidates in patients with a terminal diagnosis, who typically have exhausted standard treatment options. Commentators on the ethics of phase-1 clinical trials make diametrically opposed claims about the prospect of direct medical benefit from participation in these trials-benefits that can be attributed to receiving the experimental treatment intervention. One camp of benefit skeptics, inhabited mainly by bioethicists, characterizes this form of research as lacking any reasonable prospect of direct medical benefit. They see an ethical cloud hovering over phase-1 trials, because the vast majority of patients volunteer for phase-1 trials out of a motivation to receive medical benefit. In the view of these skeptics, such patients therefore harbor a ‘therapeutic misconception’ about research participation. This misconception calls into question the validity of informed consent and thereby undercuts the ethical basis of these trials (2). In this paper, I will discuss the ethical justification of the participation of human volunteers in phase-1 trials. (shrink)

The COVID-19 pandemic has necessitated rapid research to aid in the understanding of the disease and the development of novel therapeutics. One option is to conduct controlled human infection trials (CHITs). In this article I examine the history of deliberate human infection and CHITs and their utilization prior to the COVID-19 pandemic, key ethical considerations of CHITs in the COVID-19 setting, an analysis of the World Health Organization’s (WHO) Key criteria for the ethical acceptability of COVID-19 human (...) challenge studies, and a review of the two COVID-19 CHITs that have already commenced, their compliance with the WHO criteria and other ethical considerations. (shrink)

CHAPTER I THE REVOLT AGAINST REASON AND CONSCIENCE To MANY observers of the strange and discouraging developments of the past quarter-century, ...

The COVID-19 pandemic touched off an unprecedented search for vaccines and treatments. Without question, the development of vaccines to prevent COVID-19 was an enormous scientific accomplishment. Further, the RECOVERY and Solidarity trials identified effective treatments for COVID-19. But all was not success. The urgent need for COVID-19 prevention and treatment fueled an embrace of risks—to research participants and to the reliability of the science itself—as allegedly necessary costs to speed scientific progress. Scientists and (even) ethicists supported overturning longstanding norms protecting (...) healthy volunteers in human challenge trials to speed vaccine development, but these trials led to no vaccines. Physicians, with the approval of research ethics committees, designed hundreds of unblinded, single-center clinical trials at high risk of bias to speed the identification of new treatments. But these clinical trials led to no treatments. The lesson for future pandemics is that the acceptance of greater risks to participants or science does not reliably lead to progress. We are better served by science that upholds the highest ethical and methodological standards. (shrink)

This article engages with the vogue for predicting the effects of the Human Rights Act 1998 by focusing on the rape prosecution and trial. The specific interest is feminist scrutiny of the right to a fair trial, particularly the concept of ‘fairness’, in light of the increasing use of disclosure rules (in Canada and England) to gain access to medical and counseling records. Transcending the two contemporary narratives of ‘victims’/women’s rights and defendants’ rights in the criminal justice (...) system, the authors argue for the infusion of the legal debate on disclosure with feminist understandings of wider cultural debates. They suggest that an increased reflexivity about intimacy, publicity and power, leading perhaps to the development of a concept of ‘democratic publicity’ (Fraser, 1997, p. 100), might help to revision the meaning of ‘relevant’ evidence in the rape trial. They also suggest that the wide-ranging cultural debate about memory, truth and history, and the emerging commitment to experimentation in responding to massive, institutionalised human rights violations (including apartheid, war crimes and child abuse) might be of use in deepening current thinking about the rape trial and listening to the ‘voice’ of the complainant. (shrink)

Ex-vivo tissue engineering is an emerging medical technology. Its aim is to regenerate tissues and organs and to restore them to full physiological activity. Some clinical trials with human tissue engineered products have been conducted and others will follow. These trials not only have to confirm the therapeutic value of the HTEP, they also have to provide insight in its regenerative activity, its safety and long-term effects. The development of these trials is aggravated by the complexity of the tissue (...) engineering process and product. This paper investigates how this complexity influences the ethical conduct of clinical trials with HTEPs. We focus on the value and validity of the trial, the risk-benefit ratio and the protection of the trial participant. We argue that trials with HTEPs need a robust methodology. The risk-benefit ratio of a new HTEP must be determined and compared with available efficacious therapies. This requires the identification and minimisation of risks associated with tissue engineering. Finally a process as complex as tissue engineering presents serious challenges for the informed consent process, and for the protection of the trial participant during and after the trial. (shrink)

Research on authentic learning has been predominantly focussed on skills-based training: there is a paucity of research on models of authentic learning available for adaptation in the humanities undergraduate classroom. In this article, I will seek to address this gap by proposing that legal trials are ideal models for designing authentic learning scenarios in undergraduate teaching and learning contexts, with a specific focus on the humanities. First, I discuss why and how the structure of legal trials can produce authentic learning (...) environments. Second, I present an undergraduate classroom project that combined two disciplinary fields – Shakespearean drama and criminal law – in an effort to enhance student learning and engagement. I outline how the authentic learning scenario was implemented and evaluated and, finally, reflect on the barriers, challenges and potentially transformative effect of authentic learning environments on students and educators. This new intervention combines legal studies... (shrink)

The transition of novel and potentially promising medical therapies into their initial human clinical trials can engender conflicting pressures. On the one side, because Phase I trials raise greater ethical and human protection challenges than later stage clinical trials, there is a need to proceed cautiously. This is particularly the case for Phase I trials with a novel therapy being tested in humans for the first time, usually termed first-in-human (FIH) trials, especially if the FIH trial (...) involves significant risks. On the other side, scientists interested in having their research validated, corporations with a financial interest in the field, and potential patients and patient support groups desirous of having .. (shrink)

To reduce the global burden of the COVID-19 pandemic, there is an urgent need to develop a safe vaccine. Vaccine development usually takes many years as it goes through several different phases. To hasten COVID-19 vaccine development, it has been suggested that the final stage could be replaced with a human challenge trial. Volunteers would be intentionally infected with SARS-CoV-2 to see how the vaccine candidate works. To intentionally infect a healthy human being with a potentially deadly (...) virus is contrary to the highest ethical standards in medical research. This article highlights the benefits and risks of COVID-19 HCTs and summarises what research ethics committees need to consider during the ethical assessment of such trials including risk reduction, strict containment measures, specific informed consent measures and avoiding high monetary inducements. (shrink)

The transplantation of porcine organs to humans could in the future be a solution to the worldwide organ shortage, but is to date still highly experimental. Further research on the potential effects of crossing the species barrier is essential before clinical application is acceptable. However, many crucial questions on efficacy and safety will ultimately only be answered by well designed and controlled solid organ xenotransplantation trials on humans. This paper is concerned with the question under which conditions, given the risks (...) involved and the ethical issues raised, such clinical trials should be resumed. An alternative means of overcoming the safety and ethical issues is suggested: willed body donation for scientific research in the case of permanent vegetative status. This paper argues that conducting trials on such bodies with prior consent is preferable to the use of human subjects without lack of brain function. (shrink)

Human clinical research has become a huge economic enterprise (Morin et al. 2002; Noah 2002). Because the human subject at the center can be so easily marginalized, many commentators recommend spec...

In the transition from a repressive to a democratic society, the successor government faces the problem of how to deal with grave human rights violations such as killings and torture committed under its predecessor. This paper analyzes the dilemma a new government may encounter when it attempts to prosecute and punish those found responsible. On one hand, trials of chargeable officers may be able to prevent human rights abuses in the future and to facilitate instituting or restoring democracy. (...) On the other, in the case that there were no legal rules definitively prohibiting the abuses committed by these officers, the trials require ex post facto laws, which breach the principle of nulla poena sine lege, and more generally violate the rule of law. These retroactive laws not only break legal predictability but treat individuals unfairly. After identifying both the need for, and the legal and political losses incurred by such criminal trials, the author examines the claims that international law resolves the dilemma of retroactive justice or that prosecution is justified as a fulfillment of international obligation. Then the author refers to this dilemma as “dirty hands” to characterize a circumstance in which one cannot avoid using the wrong means to obtain the best ends. Such characterization has normative implications for three aspects of trials: the process of enacting retroactive laws and the process of conducting the trials; the choice of other possible legal remedies; and the principles related to reactions in the international community. (shrink)

The last decade or so the concept of female trafficking for the purpose of sexual exploitation has lent itself to rigorous analysis and exploration. A plethora of domestic and transnational studies and reports have attempted to address the aetiology of human trafficking, as well as its epidemiology, often drawing from sources such as statistics, narratives, documents, and observations. While the great majority of such studies are engaged, if not preoccupied, in ‘unmasking’ the particularities of sex trafficking by taking into (...) account the detection, identification, rehabilitation, and repatriation of trafficked women, the prosecution and adjudication of sex trafficking cases are often left unexamined. With this in mind, this article sets out to explore the various forces that often come into play while sex trafficking cases in Cyprus are being processed by the domestic justice system. To this end, this article considers two dimensions, the trafficked women and the judiciary. (shrink)

While new generations of implantable brain computer interface devices are being developed, evidence in the literature about their impact on the patient experience is lagging. In this article, we address this knowledge gap by analysing data from the first-in-human clinical trial to study patients with implanted BCI advisory devices. We explored perceptions of self-change across six patients who volunteered to be implanted with artificially intelligent BCI devices. We used qualitative methodological tools grounded in phenomenology to conduct in-depth, semi-structured (...) interviews. Results show that, on the one hand, BCIs can positively increase a sense of the self and control; on the other hand, they can induce radical distress, feelings of loss of control, and a rupture of patient identity. We conclude by offering suggestions for the proactive creation of preparedness protocols specific to intelligent—predictive and advisory—BCI technologies essential to prevent potential iatrogenic harms. (shrink)

In her article, Pascale Hess raises the issue of whether her proposed model may be extrapolated and applied to clinical research fields other than stem cell-based interventions in the brain (SCBI-B) (Hess 2012). Broadly summarized, Hess’s model suggests prioritizing efficacy over safety in phase 1 trials involving irreversible interventions in the brain, when clinical criteria meet the appropriate population suffering from “degenerative brain diseases” (Hess 2012). Although there is a need to reconsider the traditional phase 1 model, especially with respect (...) to first-in-human clinical trials involving novel technologies, the question arises as to whether it is appropriate to advocate for a new model that prioritizes efficacy over safety across all phase 1 clinical research trials involving irreversible interventions in the brain. -/- . (shrink)