Abstract
Research on human subjects aims to obtain knowledge of vital importance for human health and functioning. Neuroscientific research specifically is understood as oriented towards three goals: the maintenance of neurological health, the treatment of neurological diseases or syndromes, and the enhancement of neurological functioning. Most guidelines or regulations for pediatric research (whether in the U.S. or elsewhere) require that if a research intervention exposes subjects to more than minimal risk, a prospect of direct benefit is required—along with some other important criteria. It is also required for any research project, that the methods and design will yield scientifically valid knowledge. This is typically met via placebo-controlled trials. This chapter presents an argument to the effect that more than minimal risk research on pediatric subjects cannot meet both ethical requirements. The basic idea is that either the subjects in the control or experimental arm will receive a prospect of direct benefit, but not both. This chapter also argues that the ethical weight or importance of this dilemma is very acute for neuroscientific research given the complexity of the brain’s functioning and the correlated difficulty of judging whether there is a “prospect” of direct benefit. The second half responds to this argument via a case study in neuroscientific research. The solution recapitulates a type of component analysis according to which different ethical principles apply to different activities of a research study.
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Notes
- 1.
The problem I highlight in this paper should not be confused with the problem of justifying a placebo control in the setting of active treatments. Whether such studies can satisfy clinical equipoise is a different question from the one I address here. My question is this: if clinical equipoise is satisfied, can a study promise a prospect of direct benefit?
- 2.
The applicability of the moral justification is, in this case, broader than its regulatory applicability since sub-part -D governs pediatric subjects alone, not psychiatric subjects, adults suffering from neurodegenerative diseases, or mentally disabled adults, etc.
- 3.
If the evidence on the therapeutic misconception is correct, neither do adults understand the complexities of RCTs. But that fact would only argue for added protections for adults, not for taking away the subpart D protections for pediatric subjects.
- 4.
I thank an anonymous reviewer for prompting me to address these terms.
- 5.
Freedman (1987, 120) seems to think that disagreement and no consensus are synonymous as he mentions both as characterizing clinical equipoise. They are different. As I am using the term, non-consensus occurs if there is an absence of evidence to determine one way or the other, which arm of a study is better or worse overall. This can occur if the trial is a first-in-human trial or the preliminary data is based on poorly controlled pilot studies. Expert disagreement occurs if evidence exists to support differing opinions on the overall merits of the respective arms of the study. The distinction can be understood as tracking the distinction between having no evidence at all, and having ambiguous evidence.
- 6.
Potential conflict of interest disclosure: I worked for an IRB at the time it approved this study, though I was not a voting member.
- 7.
Neither the authors of the study (Marcus et al. 2013) nor commentators on it (Witmans and Shafazand 2013) mention the fact that A-T can deleteriously affect one’s immune system since the adenoids and tonsils are lymphatic organs. A-Ts are associated with a 17% increase risk for infectious diseases, and a 2–threefold increased risk for respiratory infections (Byars et al. 2018). In fairness to the CHAT researchers, these numbers were not published until 2018. However, it was known that the adenoids and tonsils make up the lymphatic organ system. It should have been anticipated that the immune system might be compromised. In any case, the facts of the Byars study place added burdens on the A-T side and brings into equilibrium the relative benefit-harm ratio between A-T and waiting.
- 8.
The reason is that moral discourse cannot proceed all the way “down” to assessing concrete actions unless the interlocutors see or feel for themselves the moral values at stake with those actions.
- 9.
The reader might find oxymoronic the idea that a researcher can expect unanticipated risks. The tension is resolved once we consider how an intellectually humble researcher would approach, for example, doing a first in-human trial.
- 10.
In a very careful and informative study, Rid and Wendler (2011) critique component analysis. They state, “The fundamental problem with different ethical requirements for therapeutic and nontherapeutic interventions is that they introduce different thresholds of acceptable net risk in biomedical research and thereby render risk-benefit evaluations incoherent. For example, “component analysis” allows competent participants to consent to sometimes significant risks without any compensating potential clinical benefits, as long as the risks result from a nontherapeutic intervention…” (2011, 148). If this is what component analysis allows, then Rid and Wendler are correct to abandon it. However, I do not think that component analysis has such consequences. As explained in the text, component analysis is measuring the various action types that take place within a research protocol against their respective moral principles. By respective moral principles I mean that certain action types are best analyzed only against certain ethical principles. For example, a person's arrogance cannot be assessed with reference to the principle of autonomy. We think arrogance is bad, yet if someone harbors supremacist views about oneself but never shares them or acts on them, no one’s autonomy is violated. The more fitting principle to assess the moral deficiency of arrogance is the principle of justice or better yet, the virtue of humility. Responding more directly to Rid and Wendler’s concerns, component analysis does not justify participants taking on significant risks without any compensating benefit. The reason is that component analysis doesn’t tell you which principles to select. It just tells you that you must select the most fitting ones. If one selects the virtue of commutative justice, component analysis does not allow competent participants to take on significant risks without any benefit (see Napier, 2019, chapter 11 for further discussion).
- 11.
Observations such as these might be where the notion of disadvantage might be useful as a marker or indicator for unjust treatment. Children who, no fault of their own, suffer from diseases with few clinical options are exposed to research projects that tolerate a higher risk than research projects on subjects with clinical options. Of course, the reason why this treatment is wrong is because it fails to treat all children as persons, and instead treats them in light of accidental features.
- 12.
Currently, whatever therapeutic modalities are being tested none of them can reverse the damage done by the progression of the disease at the time they received the modality.
- 13.
I harbor the opinion, however, that this claim is wrongheaded—which is why I title these “case based complications.” I do not think children who are at a clinical dead end can be subjects of research with a risk–benefit ratio “skewed in favor of risk” (Deakin op. cit.). That would treat children differently depending on accidental features, i.e., whether they have clinical options or not.
- 14.
The argument in this paragraph is only to the point that desolate treatment options for a small subject population is not a reason for not controlling the proposed study. There are other reasons noted above that do justify not controlling the study, namely, if the route of administration requires neurosurgery, and thus a sham control.
- 15.
I thank two anonymous referees for comments on a previous draft.
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Napier, S. (2023). Direct Benefit, Equipoise, and Research on the Non-consenting. In: Zima, T., Weisstub, D.N. (eds) Medical Research Ethics: Challenges in the 21st Century. Philosophy and Medicine, vol 132. Springer, Cham. https://doi.org/10.1007/978-3-031-12692-5_11
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