Abstract
One of the fundamental ethical concerns about biomedical research is that it frequently exposes participants to risks for the benefit of others. To protect participants’ rights and interests in this context, research regulations and guidelines set out a mix of substantive and procedural requirements for research involving humans. Risk thresholds play an important role in formulating both types of requirements. First, risk thresholds serve to set upper risk limits in certain types of research (e.g. pediatric research that offers the participating children no prospect of clinical benefit). Second, risk thresholds serve to demarcate risk categories that streamline risk-adapted systems of ethical oversight (e.g. expedited or no prospective ethical review of minimal risk research). But although risk thresholds play such an important role in research governance, there is a need both to better define the existing risk thresholds and to delineate new thresholds in order to develop more risk-adapted systems of research oversight. The present paper examines the existing minimal risk threshold and the surrounding debates with the goal of deriving a systematic approach to setting thresholds of research risk.
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Notes
For orientation, a PubMed search with the search terms ((minimal AND risk) AND ethic*) retrieved 359 publications alone on 25 April 2014 (database searched since its inception). The author reviewed these publications based on their title and identified 44 papers that directly addressed the minimal risk threshold in research involving humans.
U.S. regulations are a notable exception, as they define a small class of “beneficial” research interventions as minimal risk. These are interventions that are already marketed and used within the conditions of licensure (e.g. comparative effectiveness study of two marketed interventions). See http://www.hhs.gov/ohrp/policy/expedited98.html (accessed on 25 April 2014).
In principle, the same applies to the “scrupulous parents” standard that defines risks as minimal when informed and scrupulous parents would consent to exposing their child to these risks (Freedman et al. 1993). However, the standard assumes that scrupulous parents consider research risks as minimal when they do not exceed the risks their child faces in everyday life. Given this, relevant passages regarding the scrupulous parents standard are incorporated into the discussion of the “risks of daily life” standard that is endorsed by many regulations and guidelines (Sect. 3.3).
For a discussion of why the difference between certain burdens and potential harms (i.e. risks) is not morally salient, see (Rid and Wendler 2011).
The idea of reasonable disagreement is primarily associated with the Philosopher John Rawls who gives both an epistemological and a moral interpretation of such disagreement. On the epistemological interpretation, disagreement is reasonable if it is consistent with the proper use of reason in light of the available evidence. Unanimity cannot be reached because of various epistemic factors (e.g. conflicting empirical evidence, vague moral concepts, disagreement about relevant considerations or their weight, different ways of weighing competing considerations). On the moral interpretation, disagreement is reasonable when it is compatible with certain normative requirements (e.g. commitment to mutual justification or respect for citizens as free and equal) (Rawls 2005: lecture 2).
Constrained pure procedures are also expedient politically or institutionally, as they give decision-makers the flexibility to interpret risk thresholds in different ways.
As a reminder, the risk thresholds under discussion pertain to research procedures and studies that offer participants no prospect of clinical benefit and therefore impose risks purely for research purposes. This feature makes the relativistic interpretation of these thresholds so concerning. By contrast, a relativistic interpretation risk thresholds might be more defensible when research interventions have a prospect clinical benefit (e.g. greater risks or uncertainty might be acceptable when interventions have a prospect of benefit and participants suffer from a serious disease without alternative treatment options). For clarification, the above example assumes that the gene transfer is a “non-beneficial” intervention. This assumption seems justified given the poor track-record of gene transfer research thus far.
The uncertainty has many sources, including poor documentation of the risks of research procedures (creating uncertainty especially about low frequency events) and potential interactive effects between research procedures and other interventions administered as part of a trial (e.g. biopsies are more likely to cause bleeding when participants are treated with anti-coagulants).
More generally, risk thresholds raise intricate questions about the permissibility of balancing likelihoods and magnitudes of harm and limits on aggregate risks. It seems unlikely that reasonable people would agree about these issues. Moreover, even if they did, incorporating such agreement in regulatory or ethical guidance would most likely exceed the level of specificity with which regulations can operate.
Considered judgments are provisional fixed points in our reasoning that are characterized by a high degree of confidence in judgment (i.e. we cannot readily imagine that a considered judgment would be shaken).
Some commentators justify the reference to non-research risks on other grounds. For example, Freedman and colleagues have suggested that research risks are minimal when they displace the risks that participants would have faced in daily life absent the research (i.e. the research does not make them worse off in risk terms) (Freedman et al. 1993). The present paper does not discuss the merits of such alternative justifications for risk “comparisons”.
The example assumes that the liver biopsy would be performed purely for research purposes, which makes a relativistic interpretation of comparator risks so concerning. See also footnote 8.
One possibility is that the life of the average, healthy, normal individual has normative force because it is thought to go reasonably well. However, to the author’s best knowledge this argument has not been made and would require more scrutiny than is possible here.
For example, commentators have suggested that other features of research participation might influence risk comparisons (e.g. study participants assume risks in a principle-agent relationship (London 2006), participants passively submit to the direction of a professional who is charged with a protective responsibility towards them (Miller and Truog 2009)).
Even though some groups (e.g. infants, frail elderly) cannot actively engage in other-directed activities, they may appropriately be involved in them in a passive capacity. For example, it is appropriate for a father to take his infant on a car ride while he is taking an injured neighbor to the hospital. This suggests that the risks of other-directed activities remain a useful comparator even when the population in question cannot actively engage in these activities.
Additional uncertainty may result from the fact that the risks of specific comparator activities (e.g. playing soccer) are often poorly documented.
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Acknowledgments
Many thanks to Frank Miller and David Wendler for helpful discussion and comments. The research leading to these results has received funding from the Swiss Academy of Medical Sciences (Käthe-Zingg-Schwichtenberg Fonds 13/10) and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° 301816. A previous version of this paper was awarded the 2012 Mark S. Ehrenreich Prize in Healthcare Ethics Research (Runner-up) by the University of Southern California, Pacific Center for Health Policy and Ethics, in conjunction with the International Association of Bioethics.
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Rid, A. Setting risk thresholds in biomedical research: lessons from the debate about minimal risk. Monash Bioeth. Rev. 32, 63–85 (2014). https://doi.org/10.1007/s40592-014-0007-6
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DOI: https://doi.org/10.1007/s40592-014-0007-6