Karel MJM Caals and Calvin WL Ho
Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore
The conduct of clinical trials in low-resource settings around the world by corporations (especially those from high-income countries) has drawn a number of critical questions. A number of these relate to the adequacy and effectiveness of research oversight (if available) and of informed consent. Just as important is the question of whether such trials are exploitative? A related consideration is whether research participants or their communities received any benefit and in a measure that is fair. Arguably, the provision of fair benefit is mandated under a broad understanding of corporate social responsibility, whereby corporations are regarded as having a moral duty to confer certain benefits upon its communities at some expense to profit. Even if this duty is not disputed, we are faced with two further questions: what count as benefit, and which normative standard of fairness should apply? This paper provides a brief overview of recent ethical discussions on fair benefit in relation to clinical trials, and sets out some considerations for corporations that conduct such trials.
Reasonable Availability of Benefits
The question of how a host population should benefit from the participation of its members in research is important. Where the research population or community is one with limited resources, Guideline 10 of the International Ethical Guidelines for Biomedical Research Involving Human Subjects provides that both the sponsor and the investigator must ensure that the research is responsive to the health needs and the priorities of the population or community in which it is carried out (CIOMS 2002). In addition, the outcome of the research should be made reasonably available for the benefit of that population or community. However, the requirement of “reasonable availability” of the research – whether as intervention or product developed or as knowledge generated – for the benefit of the research population or community has been considered by some to be too lenient. For instance, it may be felt that members of a population should not be enrolled in research, particularly if health or other significant risks are entailed; in order to benefit others as this could amount to exploitation. Others consider the “reasonably available” standard to be too stringent. They are of the view that it is not always realistic or practicable for the research population or community to benefit directly from research participation. In their view, it should suffice if such participation yielded some benefits that could be deemed fair.
The “Fair Benefits” Framework
The latter view was most clearly articulated in a paper published with reference to a conference on the ethical aspects of research in developing countries that was organized by the US National Institutes of Health in 2001 (Emmanuel 2004). This approach became known as promulgating a “fair benefits” framework that is premised on three background principles: (1) research should have social value; (2) subjects should be selected fairly; and (3) research must have a favorable risk-benefit ratio. Within this framework, three additional principles are set out alongside fourteen benchmarks for determining whether the principle is honored. These additional principles are: (a) fair benefits; (b) collaborative partnership; and (c) transparency. To elaborate on the first of these additional principles, fair benefits would be determined to have been conferred provided that the following goals are met:
- Participants enjoyed health improvement or collateral health services during the research;
- Both participants and population enjoyed employment and other forms of economic gain, additional (or collateral) health services and public health measures during the research; and
- Population continues to enjoy im-provements in terms of availability of intervention (if proven effective), capacity development, additional public health measures, long-term collaboration and financial rewards (which can include intellectual property rights) after the research has concluded.
A difficulty with the fair benefits framework is its susceptibility to being relegated into a procedural assessment. By this approach, a distribution of benefits could be determined to be “fair” if the “fair benefits” goals (set out above) are met, without the need to consider if the arrangement on the whole could nevertheless be exploitative (Ballantyne 2008). While such an approach purports to take into account the contextual situation of each population or community to determine a “local standard” of “fairness”, this could be problematic where the conduct of clinical trials on a global scale is concerned. It gives rise to the problem of double standards that could be manifested in a number of ways. For instance, a research participant in a low-resource setting could be paid less on the justification of deriving benefit but without undue inducement. Another example is when a research participant in a low-resource setting receives a lower standard of care than another participant suffering from the same condition but in a high-resource setting (Macklin 2004). If justice as fairness requires that a research participant in a low-resource setting be treated no differently from another in a high-income setting, such a double standard would be hard to defend ethically. This was in fact a critique of revisions to the Declaration of Helsinki in 2002 and 2008, which allegedly sought to create such a double standard in order to accommodate the research interests of organizations in scientifically advanced and relatively prosperous countries (Solbakk 2011). Another concern is that this could lead to an auction-like structure, whereby (typically low-resource) communities or countries attempt to outbid one another, by accepting a lower share of benefit, in order to be able to host a trial (London 2010). Such a race to the bottom would superficially suggest willingness on the part of low-resource host communities or countries to participate in research, whereas in reality, well-resourced research sponsors continue to use their considerable bargaining power to capture a substantial portion of benefits from the research for high-income communities or countries (Petryna 2009).
In response, there has been a proposal for a global tax to be imposed on international research. This would enable certain benefits to be redistributed to the least-advantaged members of host communities or countries (Ballantyne 2010). However, this proposal may be practically impossible to implement for a number of reasons. First, it is unclear how the tax rate could be determined and agreed upon. Second, it is difficult to think of an effective mechanism to collect tax revenue, or to determine whom to distribute the revenue to, as well as in what form (Macklin 2010). Third, it is difficult to justify why only the pharmaceutical industry has been singled out for global taxation (Resnik 2010). Others have proposed for a rights-based approach, by which researchers could be understood as having some duty towards research participants in low-resource settings (typically developing countries) (McMillan 2010). Within a universal rights framework, benefits could in practical terms be shared fairly and sustainably by (Solbakk 2011):
- Involving stakeholders from low-resource settings (and countries) in the design, conduct and evaluation of their own national research programs;
- Giving priority to national research programs in affluent communities or countries that are expected to yield benefits which could be transferred to low resource settings or countries;
- Prioritizing national research programs that advance the human rights agenda, which includes promoting cultural diversity and pluralism;
- Facilitating capacity building in low-resources settings (and countries), which includes the establishment of a robust and independent research ethics governance body or framework;
- Contributing financially to the creation of a Global Health Research Fund that targets the research needs of low-resource communities (and countries); and
- Establishing North-South and South-South collaborations among national ethics advisory bodies.
Not all of the prescriptions within the universal rights framework apply to corporations that conduct clinical trials internationally. However, it does contribute to the substantive content of a corporation’s social responsibility, as well as to an assessment of whether it is a just organization. We recognize that there is as yet no clear resolution in the ethical literature on what should count as benefits to research participants in low-resource settings, especially where the research is sponsored by prosperous communities or countries. But there is a range of possibilities. As we have considered, it may be good enough that something is provided to the research participants, or their communities and even countries. This benefit could be monetary, or could relate to building capacity for conducting research or for other socio-economic objectives. However, one should be mindful that others have argued that the research participants or communities should benefit more directly, especially if they could derive health-related benefits from successful research. Ambiguity in the meaning of “benefits” should spur a more deliberative and reflective attitude on the part of corporations. Apart from benefit, the question of fairness will also have to be considered. Where distributive justice is concerned, Ruth Macklin (2012, page 214) indicates that two conditions must be fulfilled:
There is no fixed formula to the determination of “fair benefits” that a corporation should provide in the conduct of clinical trials internationally. However, some useful reference points are set out in this paper, and these should inform the actions of corporations.
- The design and determination of acceptable risk/benefit ratios must be evaluated with the same standards as when such research is carried out in the sponsoring country.
- Beneficiaries of the research outcomes must include people in the developing countries where the research is conducted, as well as in the developed country that sponsors the research. These conditions make it clear that it is not only the benefits and burdens accruing to the research participants but also the potentially beneficial outcomes of the research that count in determining equity.
About the Authors
Karel Caals is a research assistant at Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore. He has a degree in Tourism Management from Lessius University College, Belgium, and has extensive experience in the corporate travel industry. He is currently working on a number of projects, which include the development of an online teaching casebook on the ethics of end-of-life care, access to medicines and clinical trials. Karel’s research interests include medical travel.
Calvin WL Ho is Assistant Professor at the Centre for Biomedical Ethics in the Yong Loo Lin School of Medicine, National University of Singapore (NUS), and Research Associate with The Ethox Centre, University of Oxford. He holds a doctorate in juridical science from Cornell University, and was also trained in law at NUS and University of Cambridge. In addition, he is also trained in anthropology, sociology and economics. He recently co-edited (with Professor Terry Kaan) the monograph Genetic Privacy: An Evaluation of the Ethical and Legal Landscape (Imperial College Press, 2013). His research interests include research policy analysis, property and intellectual property rights, informational confidentiality and privacy, comparative analysis, and economic analysis of healthcare systems.
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