Characterizing the level of risk in pediatric research: an ethical examination of the federal regulations

Federal regulations require that the level of risk posed by pediatric research be classified as "minimal," "greater than minimal," or "a minor increase over minimal" Interpretation of the meaning of the levels has produced a significant literature exploring the ethical basis for making these determinations. This article examines the ethical basis of a variety of approaches proposed in the literature for classifying pediatric research risk. These approaches strive to take into account how society decides which risks are routinely accepted for children outside of research. It is concluded that ways of classifying risk should compare research risks to normal risks for children without special disability and take into account the concerns of the research subject's community.     

Effects of alcohol on variability-contingent reinforcement in human subjects

Subjects responded under LAG-5 reinforcement conditions after consuming alcohol in table wine (0.4 g/kg ethanol). For reinforcement (points), a four-response sequence from two buttons was required which differed from the previous five sequences of four responses. In addition, some subjects responded under restricted conditions in which sequences were limited to those of moving a cursor within a 3 x 3 matrix, while other subjects had no such restrictions. Also some subjects worked alone while others were accompanied by an experimenter. Analysis showed that compared to controls, men in the unrestricted condition who received alcohol showed increased uncertainty in responding while comparable women receiving alcohol showed a decrease in uncertainty of responding. The results are discussed in terms of previous work on alcohol and behavioral variability.     

Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations

United States federal regulations for pediatric research with no prospect of direct benefit restrict institutional review board (IRB) approval to procedures presenting: 1) no more than "minimal risk" ( section sign 45CFR46.404); or 2) no more than a "minor increase over minimal risk" if the research is commensurate with the subjects' previous or expected experiences and intended to gain vitally important information about the child's disorder or condition ( section sign 45CFR46.406) (DHHS 2001). During the 25 years since their adoption, these regulations have helped IRBs balance subject protections with the pursuit of scientific knowledge to advance children's welfare. At the same time, inconsistency in IRB application of these regulations to pediatric protocols has been widespread, in part because of the ambiguity of the regulatory language. During the past decade, three federally-charged committees have addressed these ambiguities: 1) the National Human Research Protections Advisory Committee (NHRPAC) (Washington, DC), 2) the Institute of Medicine (IOM) Committee on the Ethical Conduct of Clinical Research Involving Children (Washington, DC); and 3) the United States Department of Health and Human Services Secretary's Advisory Committee for Human Research Protections (SACHRP) (Washington, DC). The committees have reached similar conclusions on interpretation of language within regulations section sign section sign 45CFR46.404 and 406; these conclusions are remarkably consistent with recent international recommendations and those of the original National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) report from which current regulations are based. Drawing on the committees' public reports, this article identifies the ethical issues posed by ambiguities in regulatory language, summarizes the committees' deliberations, and calls for a national consensus on recommended criteria.     

Developing a federal policy on research misconduct

Since April 1996, the National Science and Technology Council (NSTC), in collaboration with the Office of Science and Technology Policy (OSTP) in the Executive Office of the President, has been leading the development of a government-wide Federal policy for research misconduct. The author is a Senior Policy Analyst in the Office of Science and Technology Policy and a participant in this process. This paper places the NSTC/OSTP effort in historical context, outlines the process by which the policy will be finalized, and discusses the principal issues raised during the policy development process.     

Challenging research on human subjects: justice and uncompensated harms

Ethical challenges to certain aspects of research on human subjects are not uncommon; examples include challenges to first-in-human trials (Chapman in J Clin Res Bioethics 2(4):1–8, 2011), certain placebo controlled trials (Anderson in J Med Philos 31:65–81, 2006; Anderson and Kimmelman in Kennedy Inst Ethics J 20(1):75–98, 2010) and “sham” surgery (Macklin in N Engl J Med 341:992–996, 1999). To date, however, there are few challenges to research when the subjects are competent and the research is more than minimal risk with no promise of direct benefit. The principal reason given for allowing research that is more than minimal risk without benefit is that we should respect the autonomy of competent subjects. I argue that though the moral intuitions informing respect for autonomy are sound, there is another set of intuitions regarding what we take to be just treatment of another when one agent knowingly causes or allows suffering on another agent. I argue that concerns generated by commutative justice serve as limitations on permissible research. I highlight our intuitions informing this notion of justice by appealing to work done on theodicy; what counts as a morally sufficient reason for God to allow suffering in humans is applicable also to the researcher-subject relationship. I conclude that all human subjects who are exposed to more than minimal risk research should enjoy the same actual protections (e.g., subpart D) as those given subjects who cannot consent.     

Effects and aftereffects of stressor expectations

Is stressor exposure necessary to produce "stress" effects, or can these effects result from stressor anticipation alone? The present research explores whether it is possible to obtain "stress responses" during and after the period in which stressor exposure is being anticipated. In the first study, the expectation of submerging one's hand in ice water resulted in decreased frustration tolerance and increased blood pressure when compared with control groups not expecting this stressor. A second study replicated and extended these results to show that the expectation of control over the stressor ameliorates the negative impact of stressor expectation. The second study also examined the aftereffects of expectations. Particularly, it found that despite being relieved of the expectation that they would immerse their hand in ice water, subjects who had expected stressor exposure had decreased frustration tolerance when compared with either subjects who had expected a nonstressful procedure or those who had expected to have control over stressor termination. A third study, using noise as the expected stressor, replicated both the aftereffect of the anticipation period and the moderation of that effect by perceived control. The discussion (a) focuses on the implications of this work for understanding why aftereffects occur and (b) proposes that previously observed stressor exposure effects may in fact be postexpectation effects.     

Effects of decision-making on reactions to an evaluational stressor

The present study tested the hypothesis that an opportunity to make decisions enhances perceived control. This hypothesis predicts that decision-making will reduce the adverse effects of stress. Subjects worked on an intellectual task and their stress reactions were assessed using subjective and behavioral measures. Decision-making improved the highly anxious subjects' persistence with the task. This finding supports the hypothesis. However, less anxious subjects persisted less after being allowed to make decisions. Several explanations positing possible cognitive and motivational processes of the less anxious subjects are offered.     

Use of a virtual reality car-driving stressor in cardiovascular reactivity research

Eighteen subjects (11 males, 7 females) completed a virtual reality car-driving stressor on two occasions several weeks apart. Immediately before and throughout task performance, blood pressure, cardiac output, and total peripheral resistance were assessed. Reactivity scores were calculated for each parameter for each subject as the arithmetic difference between task level and baseline level. The task elicited considerable hemodynamic activation on each occasion of testing, as well as high levels of self-reported task realism, engagement, excitement, and nervousness. Correlation analyses of both absolute and reactivity scores revealed evidence of test-retest reliability. Males were found to exhibit greater absolute levels of and greater increases in systolic blood pressure. The development of tasks suitable for inclusion in a battery of behavioral stressors, responses to which may help identify those at risk for later disease, is of considerable interest in cardiovascular behavioral medicine. The present findings suggest that the virtual reality car-driving task may be useful in this context.