Exploitations and their complications: the necessity of identifying the multiple forms of exploitation in pharmaceutical trials

Human subject trials of pharmaceuticals in low and middle income countries (LMICs) 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 (usually wealthier) 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.     

The role of trust in global health research collaborations

Collaborations in global health research are on the rise because they enhance productivity, facilitate capacity building, accelerate output and make tackling big, multifactorial research questions possible. In this paper, I examine the concepts of trust and reliance in scientific collaborations in general, but also in the particular context of collaborations in global health research between high‐income countries and low‐and‐middle income countries (LMIC). I propose and defend the argument that given the particular characteristics of collaborations and demands of trust relationships, reliance is a better relational mode for successful collaborations. Although reliance can be difficult to establish in situations where asymmetry of power exists, trust should not be the only relational mode available to LMIC researchers because of the type of vulnerability it introduces to the relationship. I conclude that the promotion of good collaborations requires addressing the power imbalances between partners, and establishing an even playing field in global health research.     

BENEFITS TO RESEARCH SUBJECTS IN INTERNATIONAL TRIALS: DO THEY REDUCE EXPLOITATION OR INCREASE UNDUE INDUCEMENT?

There is an alleged tension between undue inducement and exploitation in research trials. This paper considers claims that increasing the benefits to research subjects enrolled in international, externally‐sponsored clinical trials should be avoided on the grounds that it may result in the undue inducement of research subjects. It proceeds from the premise that there are good grounds for thinking that, at least some, international research sponsors exploit trial participants because they do not provide the research population with a fair share of the benefits of research. This provides a prima facie argument for increasing the benefits for research participants. Concern over undue inducement is a legitimate moral concern; however, if this concern is to prevent research populations from receiving their fair share of benefits from research there must be sufficient evidence that these benefits will unduly influence patients’ decision‐making regarding trial participation. This article contributes to the debate about exploitation versus undue inducement by introducing an analysis of the available empirical research into research participants’ motivations and the influence of payments on research subjects’ behaviour and risk assessment. Admittedly, the available research in this field is limited, but the research that has been conducted suggests that financial rewards do not distort research subjects’ behaviour or blind them to the risks involved with research. Therefore, I conclude that research sponsors should prioritise the prevention of exploitation in international research by providing greater benefits to research participants.     

Randomised Placebo-controlled trials and HIV-infected Pregnant Women in Developing Countries. Ethical Imperialism or Unethical Exploitation

The maternal-fetal HIV transmission trials, conducted in developing countries in the 1990s, undoubtedly generated one of the most intense, high profile controversies in international research ethics. They sparked off a prolonged acrimonious and public debate and deeply divided the scientific community. They also provided an impetus for the revision of the Declaration of Helsinki – the most widely known guideline for international research. In this paper, I provide a brief summary of the context, outline the arguments for and against the controversial use of placebo controls, and focus on particular areas that I believe merit further discussion or clarification. On balance, I argue that the researchers failed in their duties to protect the best interests of their research subjects, and to promote distributive justice. I discuss the difficulties of obtaining valid consent in this research context, and argue that it is unethical to inform women of their HIV status without at least offering them prophylactic treatment for their unborn children. A global view of justice, which endorses international equity, cannot be squared with international research guidelines that allow 'local conditions' to define the scope of duty to the control group. Finally, I suggest that the heated debate reflects a tension, if not an outright war, between two conflicting meta-ethical systems, or incommensurable paradigms, that underpin scientific research involving human subjects.     

Managing Human Tissue Transfer Across National Boundaries – An Approach from an Institution in South Africa

With biobank research on the increase and the history of exploitation in Africa, it has become necessary to manage the transfer of human tissues across national boundaries. There are many accepted templates of Material Transfer Agreements (MTAs) that currently exist internationally. However, these templates do not address the specific concerns of South Africa and even of Africa as a continent. This article will examine three significantly important ethico‐legal concepts that were deliberated and carefully adapted by a South African Institution to suit the transfer of Human Biological Materials (HBMs) and associated data for biobank research, namely: informed consent; benefit sharing arrangements; and ownership together with intellectual property rights in human tissues. The discussion includes an analysis of current practice; the ethico‐legal challenges in the South African/African context; the decisions made with regard to how the related ethico‐legal challenges were addressed in the MTA; and justifications for implementing these decisions. The processes considered could be of benefit to other developing world countries who consider it necessary to manage the transfer of HBMs across national boundaries.     

Investigating assumptions of vulnerability: A case study of the exclusion of psychiatric inpatients as participants in genetic research in low‐ and middle‐income contexts

Psychiatric genetic research investigates the genetic basis of psychiatric disorders with the aim of more effectively understanding, treating, or, ultimately, preventing such disorders. Given the challenges of recruiting research participants into such studies, the potential for long‐term benefits of such research, and seemingly minimal risk, a strong claim could be made that all non‐acute psychiatric inpatients, including forensic and involuntary patients, should be included in such research, provided they have capacity to consent. There are tensions, however, regarding the ethics of recruiting psychiatric inpatients into such studies. In this paper our intention is to elucidate the source of these tensions from the perspective of research ethics committee interests and decision‐making. We begin by defining inpatient status and outline some of the assumptions surrounding the structures of inpatient care. We then introduce contemporary conceptions of vulnerability, including Florencia Luna’s account of vulnerability which we use as a framework for our analysis. While psychiatric inpatients could be subject to consent‐related vulnerabilities, we suggest that a particular kind of exploitation‐related vulnerability comes to the fore in the context of our case study. Moreover, a subset of these ethical concerns takes on particular weight in the context of genetic research in low‐ and middle‐income countries. At the same time, the automatic exclusion of inpatients from research elicits justice‐related vulnerabilities.     

Why and How to Compensate Living Organ Donors: Ethical Implications of the New Australian Scheme

The Australian Federal Government has announced a two‐year trial scheme to compensate living organ donors. The compensation will be the equivalent of six weeks paid leave at the rate of the national minimum wage. In this article I analyse the ethics of compensating living organ donors taking the Australian scheme as a reference point. Considering the long waiting lists for organ transplantations and the related costs on the healthcare system of treating patients waiting for an organ, the 1.3 million AUD the Australian Government has committed might represent a very worthwhile investment. I argue that a scheme like the Australian one is sufficiently well designed to avoid all the ethical problems traditionally associated with attaching a monetary value to the human body or to parts of it, namely commodification, inducement, exploitation, and equality issues. Therefore, I suggest that the Australian scheme, if cost‐effective, should represent a model for other countries to follow. Nonetheless, although I endorse this scheme, I will also argue that this kind of scheme raises issues of justice in regard to the distribution of organs. Thus, I propose that other policies would be needed to supplement the scheme in order to guarantee not only a higher number of organs available, but also a fair distribution.     

From protectionism to inclusion: A New Zealand perspective on health‐related research involving adults incapable of giving informed consent

The revision of the Council of International Organizations of Medical Sciences (CIOMS) International ethical guidelines for health‐related research (2016) heralds a paradigm shift from the ‘protectionist’ policies that emerged following historical research atrocities of the 20th century, towards a more nuanced and inclusive approach to research participation. Adopting this modified approach will enable countries to secure the benefits of research for individuals and for society as a whole, while at the same time minimizing the potential for exploitation and research‐related harms. This article considers the potential impact of Guideline 16 of the CIOMS 2016 from a New Zealand perspective, with respect to research involving adults with impaired capacity and who are incapable of giving informed consent. While the CIOMS 2016 apply a ‘minimal risk’ threshold to guide research involving adults who lack capacity to consent, New Zealand law currently adopts a ‘best interests’ standard which significantly restricts the scope of permissible research that may be performed in this context. This article argues that the CIOMS 2016 should influence change to New Zealand’s legal framework for ethical review of research. CIOMS 2016 provides useful guidance for the necessary standards and processes to enable the responsible and ethical inclusion of adults with impaired capacity in research.     

Sweet host revenge: Galectins and GBPs join forces at broken membranes

Most bacterial pathogens enter and exit eukaryotic cells during their journey through the vertebrate host. In order to endure inside a eukaryotic cell, bacterial invaders commonly employ bacterial secretion systems to inject host cells with virulence factors that co‐opt the host's membrane trafficking systems and thereby establish specialised pathogen‐containing vacuoles (PVs) as intracellular niches permissive for microbial growth and survival. To defend against these microbial adversaries hiding inside PVs, host organisms including humans evolved an elaborate cell‐intrinsic armoury of antimicrobial weapons that include noxious gases, antimicrobial peptides, degradative enzymes, and pore‐forming proteins. This impressive defence machinery needs to be accurately delivered to PVs, in order to fight off vacuole‐dwelling pathogens. Here, I discuss recent evidence that the presence of bacterial secretion systems at PVs and the associated destabilisation of PV membranes attract such antimicrobial delivery systems consisting of sugar‐binding galectins as well as dynamin‐like guanylate‐binding proteins (GBPs). I will review recent advances in our understanding of intracellular immune recognition of PVs by galectins and GBPs, discuss how galectins and GBPs control host defence, and highlight important avenues of future research in this exciting area of cell‐autonomous immunity.     

An Update to Returning Genetic Research Results to Individuals: Perspectives of the Industry Pharmacogenomics Working Group

The ease with which genotyping technologies generate tremendous amounts of data on research participants has been well chronicled, a feat that continues to become both faster and cheaper to perform. In parallel to these advances come additional ethical considerations and debates, one of which centers on providing individual research results and incidental findings back to research participants taking part in genetic research efforts. In 2006 the Industry Pharmacogenomics Working Group (I‐PWG) offered some ‘Points‐to‐Consider’ on this topic within the context of the drug development process from those who are affiliated to pharmaceutical companies. Today many of these points remain applicable to the discussion but will be expanded upon in this updated viewpoint from the I‐PWG. The exploratory nature of pharmacogenomic work in the pharmaceutical industry is discussed to provide context for why these results typically are not best suited for return. Operational challenges unique to this industry which cause barriers to returning this information are also explained.     

No trade‐offs in interspecific interference ability and predation susceptibility in newt larvae

Coexistence of species with similar requirements is allowed, among others, through trade‐offs between competitive ability and other ecological traits. Although interspecific competition is based on two mechanisms, exploitation of resources and physical interference, trade‐off studies largely consider only species’ ability to exploit resources. Using a mesocosm experiment, we examined the trade‐off between interference competition ability and susceptibility to predation in larvae of two newt species, Ichthyosaura alpestris and Lissotriton vulgaris. In the presence of heterospecifics, L. vulgaris larvae slowed somatic growth and developmental rates, and experienced a higher frequency of injuries than in conspecific environments which suggests asymmetrical interspecific interference. During short‐term predation trials, L. vulgaris larvae suffered higher mortality than I. alpestris. Larvae of the smaller species, L. vulgaris, had both lower interference and antipredator performance than the larger I. alpestris, which suggests a lack of trade‐off between interference competition ability and predator susceptibility. We conclude that interference competition may produce a positive rather than negative relationship with predation susceptibility, which may contribute to the elimination of subordinate species from common habitats.     

Corruption and research

Last year there was a heated debate regarding clinical trials with AZT carried out in developing countries. AIDs vaccine trials also posed various dilemmas and ethical problems. In this paper I will consider the possibility of corruption in bioethics, and international multi-centre research will be taken as an example. International clinical trials will be seen from another perspective. I will try to show that the possibility of systemic corruption should be considered when designing an international multi-centre research trial which may involve countries in very different situations regarding corruption. I will analyze three different approaches to this problem and suggest some strategies regarding their capacity to exclude the possibility of corruption.     

Virulence evolution and the trade‐off hypothesis: history,current state of affairs and the future

It has been more than two decades since the formulation of the so‐called ‘trade‐off’ hypothesis as an alternative to the then commonly accepted idea that parasites should always evolve towards avirulence (the ‘avirulence hypothesis’). The trade‐off hypothesis states that virulence is an unavoidable consequence of parasite transmission; however, since the 1990s, this hypothesis has been increasingly challenged. We discuss the history of the study of virulence evolution and the development of theories towards the trade‐off hypothesis in order to illustrate the context of the debate. We investigate the arguments raised against the trade‐off hypothesis and argue that trade‐offs exist, but may not be of the simple form that is usually assumed, involving other mechanisms (and life‐history traits) than those originally considered. Many processes such as pathogen adaptation to within‐host competition, interactions with the immune system and shifting transmission routes, will all be interrelated making sweeping evolutionary predictions harder to obtain. We argue that this is the heart of the current debate in the field and while species‐specific models may be better predictive tools, the trade‐off hypothesis and its basic extensions are necessary to assess the qualitative impacts of virulence management strategies.     

Reinterpreting Responsiveness for Health Systems Research in Low and Middle‐Income Countries

The ethical concept of responsiveness has largely been interpreted in the context of international clinical research. In light of the increasing conduct of externally funded health systems research (HSR) in low‐ and middle‐income countries (LMICs), this article examines how responsiveness might be understood for such research and how it can be applied. It contends that four features (amongst others) set HSR in LMICs apart from international clinical research: a focus on systems; being context‐driven; being policy‐driven; and being closely linked to development objectives. These features support reinterpreting responsiveness for HSR in LMICs as responsiveness to systems needs, where health system performance assessments can be relied upon to identify systems needs, and/or responsiveness to systems priorities, which entails aligning research with HSR priorities set through country‐owned processes involving national and sub‐national policymakers from host countries. Both concepts may be difficult to achieve in practice. Country ownership is not an established fact for many countries and alignment to their priorities may be meaningless without it. It is argued that more work is, therefore, needed to identify strategies for how the responsiveness requirement can be ethically fulfilled for HSR in LMICs under non‐ideal conditions such as where host countries have not set HSR priorities via country‐owned processes. Embeddedness is proposed as one approach that could be the focus of further development.     

The cost of phage resistance in a plant pathogenic bacterium is context‐dependent

Parasites are ubiquitous features of living systems and many parasites severely reduce the fecundity or longevity of their hosts. This parasite‐imposed selection on host populations should strongly favor the evolution of host resistance, but hosts typically face a trade‐off between investment in reproductive fitness and investment in defense against parasites. The magnitude of such a trade‐off is likely to be context‐dependent, and accordingly costs that are key in shaping evolution in nature may not be easily observable in an artificial environment. We set out to assess the costs of phage resistance for a plant pathogenic bacterium in its natural plant host versus in a nutrient‐rich, artificial medium. We demonstrate that mutants of Pseudomonas syringae that have evolved resistance via a single mutational step pay a substantial cost for this resistance when grown on their tomato plant hosts, but do not realize any measurable growth rate costs in nutrient‐rich media. This work demonstrates that resistance to phage can significantly alter bacterial growth within plant hosts, and therefore that phage‐mediated selection in nature is likely to be an important component of bacterial pathogenicity.     

Meta‐analysis indicates that oxidative stress is both a constraint on and a cost of growth

Oxidative stress (OS) as a proximate mechanism for life‐history trade‐offs is widespread in the literature. One such resource allocation trade‐off involves growth rate, and theory suggests that OS might act as both a constraint on and a cost of growth, yet studies investigating this have produced conflicting results. Here, we use meta‐analysis to investigate whether increased OS levels impact on growth (OS as a constraint on growth) and whether greater growth rates can increase OS (OS as a cost of growth). The role of OS as a constraint on growth was supported by the meta‐analysis. Greater OS, in terms of either increased damage or reduced levels of antioxidants, was associated with reduced growth although the effect depended on the experimental manipulation used. Our results also support an oxidative cost of growth, at least in terms of increased oxidative damage, although faster growth was not associated with a change in antioxidant levels. These findings that OS can act as a constraint on growth support theoretical links between OS and animal life histories and provide evidence for a growth–self‐maintenance trade‐off. Furthermore, the apparent oxidative costs of growth imply individuals cannot alter this trade‐off when faced with enhanced growth. We offer a starting platform for future research and recommend the use of oxidative damage biomarkers in nonlethal tissue to investigate the growth–OS relationship further.     

Rights, indirect harms and the non-identity problem

The non‐identity problem is the problem of grounding moral wrongdoing in cases in which an action affects who will exist in the future. Consider a woman who intentionally conceives while on medication that is harmful for a fetus. If the resulting child is disabled as a result of the medication, what makes the woman's action morally wrong? I argue that an explanation in terms of harmful rights violations fails, and I focus on Peter Markie's recent rights‐based defense. Markie's analysis rests on the notion of an indirect harm, and I show that the calculation of an indirect harm relies on an improper baseline for the determination of whether or not an action adversely affects a patient's interests. I also defend an impersonal duty‐based analysis of the wrongdoing in non‐identity cases against an objection by Markie. I close by arguing that the rights‐based analysis is insensitive to context and that context is morally relevant in the determination of the moral valence of actions in cases of non‐identity. This failure provides a pro tanto reason to favor an impersonal duty‐based analysis of the wrongdoing in non‐identity cases.     

Cost of Female Intrasexual Aggression in Terms of Offspring Quality: A Cross‐Fostering Study

Growing evidence that female ornaments and armaments may be important for female reproductive success suggests that a reevaluation of the costs of these potentially sexually selected traits is also necessary. Here, I examine whether intrasexual aggression, a trait favored during direct female–female competition for nesting sites in tree swallows (Tachycineta bicolor), is costly in terms of the quantity or quality of offspring. I compared measures of female aggressiveness to clutch size, and I also cross‐fostered offspring just after hatching to explore a possible causal link between female aggression and nestling mass, an established proxy for offspring quality. High levels of aggression in females were not associated with the quantity of offspring, but instead more aggressive females had offspring of lower quality. While several causal factors appear to influence offspring quality, the mechanism most consistent with this cost of aggression is a trade‐off between female aggression and aspects of maternal care. Site differences may create variation in how selection shapes female aggression, but the finding that more aggressive females had lower‐quality control offspring indicates that this cost may work counter to selection favoring aggressive behavior in the context of competition over nestboxes.     

The Social Value of Knowledge and International Clinical Research

In light of the growth in the conduct of international clinical research in developing populations, this paper seeks to explore what is owed to developing world communities who host international clinical research. Although existing paradigms for assigning and assessing benefits to host communities offer valuable insight, I criticize their failure to distinguish between those benefits which can justify the conduct of research in a developing world setting and those which cannot. I argue that the justification for human subjects research is fundamentally grounded in the social value of knowledge, and that this value is context‐dependent in a manner which should inform our ethical evaluation of the conduct of research in specific settings. I propose a new framework for the assessment of research benefits assigned to developing world host communities, a natural implication of which is to limit the types of research projects which may permissibly be conducted in developing world settings.