2.5 Ethical issues in international biomedical research
2.5.6 Favourable risk/benefit ratio
The risk/benefit assessment of research protocols by RECs is an important component of ethics review in accordance with the ethical principles of beneficence and nonmaleficence (Emanuel et al., 2004; Weijer, 2000). RECs are required to conduct a systematic, non-arbitrary assessment of the potential risks and benefits of a research protocol insofar as these are foreseeable (Belmont Report, 1979). The US Common Rule requires that in order for research to be approved, IRBs should ensure that “(1) Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. (2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be
expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility” (DHHS, 1991 p. 40).
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While the importance of favourable risk/benefit ratio is highlighted by several international and national ethical guidelines and frameworks (Emanuel et al., 2004), there is considerable debate regarding when are research risks reasonable in relation to anticipated benefits (Weijer & Miller, 2004), and what conceptual framework should guide the ethical analysis of risk (Weijer, 2000).
There are two leading models that have been proposed for a systematic approach to risk/benefit assessment, i.e., the component analysis and the net risks analysis (Weijer, 2000; Weijer &
Miller, 2004). According to Weijer (2000) a component-based approach to risk/benefit assessment involves analysis of both a) the magnitude of the harm and b) its probability of occurrence. The component analysis approach is premised on the recognition that biomedical research often consists of a combination of therapeutic and non-therapeutic components, and as such there is need for separate moral standards for the assessment of individual study
components or research intervention or procedure involved in a particular study instead of conducting a global risk benefit analysis profile of the overall study (Weijer, 2000).
However, opponents of the component approach have argued that the approach is flawed for several reasons. They argue that, equipoise, one of the concepts of the component analysis approach, conflates ethics of research with ethics of clinical care (Miller & Brody, 2003).
Furthermore, opponents argue that the component approach is inappropriately applied in the ethical analysis of placebo-controls (Emanuel & Miller, 2001). Wendler and Miller (2007) proposed the net risks test as an alternative approach for risk/benefit assessment. Similar to the component analysis, the net risks test’s emphasis is on consideration of the risks and benefits of individual research procedures or interventions instead of the overall study. However, there is a fundamental difference in the normative foundation of the net risks test which distinguishes it
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from the component analysis. The net risks test is premised on the fundamental principle of non- exploitation, a central concept in the ethics of clinical research. Thus, the primary objective of the net risks test (and risk/benefit assessment in general) is to safeguard the protection of research participants from being exposed to excessive risks of harm for the benefit of others.
There are four ethical requirements articulated by the net risks test. First, the risks posed by each individual study procedure should be minimized, and the potential benefits of each procedure must be enhanced. Second, a research procedure should not pose an excessive increase in risk or an excessive decrease in potential clinical benefit for the participant when compared to available alternatives. In other words, this second requirement encompasses an assessment of whether a particular research procedure presents net risk to the individual research participant, followed by an assessment of whether these risks are excessive (Wendler & Miller, 2007). Net risks could occur in at least two scenarios. For instance, where the risks of a particular study procedure or intervention exceed its potential clinical benefits for the participant, then there is a net risk. An example of this scenario is in Phase I oncology trials, where the drugs often pose more risks to the participant than they offer potential benefits (Rid & Wendler, 2010). Another scenario of net risks occurs when a research procedure poses risks that do not exceed the procedure’s potential clinical benefits, but the procedure’s risk/benefit profile is lower than the risk/benefit profile of one or more of the available alternatives. For example, some older generation drugs offer a favourable risk/benefit ratio, but then it is lower than the risk/benefit ratio of newer drugs with which they have been replaced. Where a particular study procedure poses net risks to participants (as in the examples above), the net risks test necessitates that these risks are sufficiently low (Rid
& Wendler, 2010).
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The third requirement of the net risks test is that where a study procedure poses net risk, this should be justified by the knowledge expected to be gained from using that particular study procedure. This requirement is important in ensuring that the net risks to an individual research participant, on the provision that they are not excessive, are reasonable in relation to potential societal benefits (Wendler & Miller, 2007). The last requirement of the net risks test is that the
‘cumulative’ net risks of all the combined research procedures (regardless of whether each procedure poses low net risks to participants) in a study should not be excessive (Wendler &
Miller, 2007, p. 484).
Critics of the net risk test argue that the approach has limitations in that it fails to align the ethics that govern clinical research with those of clinical care, subsequently allowing research that violates patients’ rights to appropriate care (Weijer & Miller, 2007). Another criticism of the net risks test is that it permits any level of risk, as long as the anticipated benefits to society are reasonable, and thus may undermine the public trust of the medical research enterprise (Weijer &
Miller, 2007). Furthermore, the net risks test is criticized for its apparent lack of definition of
‘excessive’ risk, hence leaving it to the discretion of RECs to make the determination of what risks are excessive (Weijer & Miller, 2007). This may cause variability in how RECs make decisions regarding the risk/benefit ratio of a study (Shah et al., 2004).
Bernabe, van Thiel, Raaijmakers and van Delden (2012) argue that both procedure-level approaches conflate the various risk/benefit assessment tasks of RECs.This conflation, the authors claim, makes the REC’s task of assessing the risk/benefit of a research “confusing, if not impossible” (p.8). Rid (2014) argues that the current model for risk/benefit assessment is not
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comprehensive and arguably places too much emphasis on informed consent as a condition of acceptable net risk to participants. Rid proposes that the scientific and social value of biomedical research is likely to be fundamental to the acceptability of exposing participants to net research risks. This implies that when a particular study is scientifically valid and socially valuable, then it may be justifiable to expose participants to net risks of research (Rid, 2014).