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.     

Risks and Benefits of Pediatric Bone Marrow Donation: A Critical Need for Research

Healthcare providers assume that there are minimal risks and potential psychosocial benefits for children who undergo a bone marrow harvest for the benefit of their critically ill siblings. Ethical justifications for the use of children as donors rely on there being minimal risks since donors receive no direct medical benefits from the intervention. There is little empirical research regarding psychosocial consequences. This article reviews relevant research in three contexts: a) psychosocial outcomes for adults and children who donate tissue and organs; b) psychosocial impacts on a sibling of a pediatric cancer patient; and c) children's decision-making regarding medical decisions. The relevant research literature supports the belief that the psychosocial impact on a child bone marrow donor will be influenced by the survival of the recipient, the age of the donor, and the donor's participation in the decision to donate. In order to empirically validate the actual psychosocial risks (and benefits) for donors, it is argued that direct research is needed so that a donor's well-being can be protected.     

On the Limits of Parental Proxy Consent: Children's Right to Non-Participation in Non-Therapeutic Research

This paper considers what are the appropriate limits of parental or guardian proxy consent for a child's participation in medical or social science research. Such proxy consent, it is proposed, is invalid in regards “non-therapeutic research.” The latter research may add to scientific knowledge and/or benefit others, but any benefit to the child research participant is but a coincidental theoretical possibility and not a primary objective. Research involving children, without intended and acceptable prospect of beneficial outcome to the individual participant, even if with negligible risk, does not meet the test for “best interests.” Proxy consent for children's involvement in research is justifiable only when given for and on behalf of the child in his or her best interest to enhance the child's well-being. Only in the latter case is the parental proxy consent situation analogous in regards key criteria to a competent individual consenting to research participation. This revised version was published online in August 2006 with corrections to the Cover Date.     

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.     

Should children decide whether they are enrolled in nonbeneficial research?

The U.S. federal regulations require investigators conducting nonbeneficial research to obtain the assent of children who are capable of providing it. Unfortunately, there has been no analysis of which children are capable of assent or even what abilities ground the capacity to give assent. Why should investigators be required to obtain the positive agreement of some children, but not others, before enrolling them in research that does not offer a compensating potential for direct benefit? We argue that the scope of children's research decision making should be based on the principles of respect for autonomy and nonmaleficence. These principles imply that the threshold for assent should be fixed at 14 years of age, and a dissent requirement should be adopted for all children in the context of nonbeneficial research.     

From Intent to Enrollment,Attendance, and Participation in Preventive Parenting Groups

Applying the Theory of Planned Behavior (TPB) to the process of engagement in preventive parenting groups, we tested the ability of family and child measures to predict intent to enroll, enrollment, attendance, and quality of participation in PACE (Parenting Our Children to Excellence). PACE is a prevention trial testing the efficacy of a structured program to promote effective parenting and reduce risk of adverse child outcomes. Mothers of preschoolers (N=451) from diverse ethnic and socioeconomic backgrounds participated at two sites. Results showed that mothers who stated their intent to enroll reported relatively few time constraints but high levels of stress, as did mothers who enrolled. The latter also experienced elevated levels of oppositional defiant child behaviors, indicating that the program reached families who stood to benefit from it. Attendance, which was also best predicted by few time constraints, was high (with 49% of mothers who enrolled attending 5 or more of 8 sessions). In turn, attendance predicted quality of participation (at 1 site only), with mothers attending more sessions participating more actively and enthusiastically. Ethnicity and, with a few exceptions, socioeconomic circumstances and site, were not significant predictors of intent, enrollment, or attendance. Results provide qualified support for the TPB and illustrate its relevance to preventive research and interventions.     

A new justification for pediatric research without the potential for clinical benefit

Pediatric research without the potential for clinical benefit is vital to improving pediatric medical care. This research also raises ethical concern and is regarded by courts and commentators as unethical. While at least 10 justifications have been proposed in response, all have fundamental limitations. This article describes and defends a new justification based on the fact that enrollment in clinical research offers children the opportunity to contribute to a valuable project. Contributing as children to valuable projects can benefit individuals in two ways. First, individuals may come to "embrace" the contributions they made as children. Second, contributing to valuable projects can lead to a better overall life. Because these potential benefits can outweigh small research risks, they provide a justification for pediatric research without the potential for clinical benefit, when it poses low risks and has the potential to benefit others in important ways.     

Limits on risks for healthy volunteers in biomedical research

Healthy volunteers in biomedical research often face significant risks in studies that offer them no medical benefits. The U.S. federal research regulations and laws adopted by other countries place no limits on the risks that these participants face. In this essay, I argue that there should be some limits on the risks for biomedical research involving healthy volunteers. Limits on risk are necessary to protect human participants, institutions, and the scientific community from harm. With the exception of self-experimentation, limits on research risks faced by healthy volunteers constitute a type of soft, impure paternalism because participants usually do not fully understand the risks they are taking. I consider some approaches to limiting research risks and propose that healthy volunteers in biomedical research should not be exposed to greater than a 1% chance of serious harm, such as death, permanent disability, or severe illness or injury. While this guideline would restrict research risks, the limits would not be so low that they would prevent investigators from conducting valuable research. They would, however, set a clear upper boundary for investigators and signal to the scientific community and the public that there are limits on the risks that healthy participants may face in research. This standard provides guidance for decisions made by oversight bodies, but it is not an absolute rule. Investigators can enroll healthy volunteers in studies involving a greater than 1% chance of serious harm if they show that the research addresses a compelling public health or social problem and that the risk of serious harm is only slightly more than 1%. The committee reviewing the research should use outside experts to assess these risks.     

Bonus Allocation Points for Those Willing to Donate Organs

The U.S. federal regulations require investigators conducting nonbeneficial research to obtain the assent of children who are capable of providing it. Unfortunately, there has been no analysis of which children are capable of assent or even what abilities ground the capacity to give assent. Why should investigators be required to obtain the positive agreement of some children, but not others, before enrolling them in research that does not offer a compensating potential for direct benefit? We argue that the scope of children's research decision making should be based on the principles of respect for autonomy and nonmaleficence. These principles imply that the threshold for assent should be fixed at 14 years of age, and a dissent requirement should be adopted for all children in the context of nonbeneficial research.     

A starting point for consciousness research: Reply to Thomas Schmidt

Anesthesia research has focused on showing learning in the absence of awareness for good practical reasons. Crucially, continued learning during otherwise clinically adequate anesthesia may affect patients’ well-being on recovery. Theoretically, preserved perceptual priming during anesthesia offers a useful starting point for consciousness research by determining the limits of memory function during minimal (if not absent) consciousness. The big question for consciousness research is not to demonstrate absolutely unconscious processing, but rather to map out the cognitive and neurobiological processes that enable conscious experience itself.     

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.     

Orangutans (Pongo abelii) "play the odds": information-seeking strategies in relation to cost, risk, and benefit

Recent research has examined whether animals possess metacognition, or the ability to monitor their knowledge states. However, the extent to which animals actively control their knowledge states is still not well delineated. Although organisms might be capable of seeking information when it is lacking, it does not mean that it is always adaptive to do so. In the present set of experiments, we examined the flexibility of this behavior in captive orangutans (Pongo abelii; two adults and one juvenile) in a foraging task, by varying the necessity of information-seeking, the cost associated with it, the likelihood of error, and the value of the reward. In Experiment 1, subjects searched for information most often when it was "cheapest" energetically. In Experiment 2, subjects searched for information most often when the odds of making an error were the greatest. In Experiment 3, subjects searched for information more when the reward was doubled in value. In Experiment 4, adult subjects adapted to risk/benefit trade-offs in their searching behavior. In every experiment, subjects sought information more often when they needed it than when they already knew the solution to the problem. Therefore, the current research suggests that information-seeking behavior in orangutans shows a sophisticated level of flexibility, comparable to that seen in human children, as they appear to "play the odds" when making the decision to seek information or not.     

Gratitude and parents' rights over their children's religious upbringing

Although most parents claim their children owe them obligations of gratitude, there has been no attempt to analyze gratitude as a basis for parental rights over children's religious upbringing. Parents' provision of benefits to their children in an altruistic fashion requires that children ought normally to honor parental requests that they participate in religious rituals and attend sectarian education. However, the limits on parental altruism and the self‐defeating nature of extreme demands for requital of gratitude suggest that gratitude is not a sufficiently strong basis to justify the rights of parents to prevent their children's exposure to religious beliefs inconsistent with their own. The state acts consistently with children's obligation of gratitude when it offers an education providing children the right to exit their religious communities, but not when it seeks to promote radical religious autonomy.     

Strategy development and learning to spell new words: generalization of a process

The authors used microgenetic methods in 2 experiments to examine children's and adults' progress from initial attempts at spelling nonwords to later direct memory retrieval of the spellings. Participants repeatedly spelled nonwords presented in computerized, dictated-word spelling tests over several weeks. Following each spelling, participants provided retrospective strategy reports. Half of the children showed a gradual shift from spelling words with effortful backup strategies to fast retrieval; half of the children continued using backup strategies that were fast and effective for them. Relatively more adults shifted from backup strategies to retrieval, but otherwise their patterns of spelling development were quite similar to those of the children. This research provides support for the generalizability of the overlapping waves model to nonalgorithmic domains. It also demonstrates parallels between children and adults in learning to spell new words.     

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” (§ 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 (§ 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 § § 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) National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1977. Report and recommendations: Research involving children, Washington, DC: U.S. Government Printing Office.  [Google Scholar] 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.     

Composition as Identity Doesn’t Settle the Special Composition Question1

Orthodoxy says that the thesis that composition is identity (CAI) entails universalism: the claim that any collection of entities has a sum. If this is true it counts in favour of CAI, since a thesis about the nature of composition that settles the otherwise intractable special composition question (SCQ) is desirable. But I argue that it is false: CAI is compatible with the many forms of restricted composition, and SCQ is no easier to answer given CAI than otherwise. Furthermore, in seeing why this is the case we reveal an objection to CAI: that it allows for the facts concerning what there is to be settled whilst leaving open the question about what is identical to what.     

Processing ambiguous Spanish se in a minimal chain

The recovery of pieces of information that are not linguistically expressed is a constant feature of the process of language comprehension. In the processing literature, such missing information is generally referred to as "gaps". Usually, one resolves gaps by finding "fillers" in either the sentence or the context. For instance, in Peter seemed to be upset, Peter is really the subject of being upset but appears as surface subject of seems. Sometimes constituents move, leaving gaps behind. Various Romance languages such as Spanish or Italian have a grammatical particle se/si, which, as it is extremely ambiguous, licenses different sorts of gaps. In Spanish, se can encode at least reflexive, impersonal, and passive meanings. In an eye-tracking experiment we contrast reflexive structures containing postverbal subjects with impersonal structures with no subjects (GAP se vendó apresuradamente el corredor/"the runner bandaged himself hurriedly" vs. GAP se vendó apresuradamente al corridor/"(someone) bandaged the runner hurriedly"). In a second manipulation we contrast the presence of an extra argument with se-passives (GAP se vendó el tobillo el corredor/"the runner bandaged his ankle" vs. GAP se vendó el tobillo al corridor/"the runner's ankle was bandaged"). Our comparisons involve contrasting standard transitive structures with nonstandard word order (postverbal subject and a preverbal subject gap) against inherently complex and less habitual structures such as impersonals (with no subject) or se-passives (with subjects in canonical object position). We evaluate the minimal chain principle (de Vincenzi, 1991), according to which displacement is costly because it entails complex (derivational) "chains" that must be undone before phrasal packaging can commence. We show the minimal chain principle to be essentially correct when contrasting more complex but more frequent structures with less complex but less frequent structures. A noteworthy feature of this research is that the gaps appear before the fillers in the structures that we analyse.     

A qualitative examination of the work–family interface: Parents of children with autism spectrum disorder

Within the work–family literature little is known about the work–family challenges and opportunities faced by families that have one or more children with autism spectrum disorder. However, it has been consistently demonstrated that parents of children with autism spectrum disorder are at a higher risk of experiencing a host of negative outcomes. Using a qualitative design, within grounded theory, the present study sheds light on the needs, experiences, and challenges that parents of children with autism spectrum disorder face and also offers insight into ways to expand the scope of work–family research in this area. The present research provides evidence of how the family domain can greatly impact experiences and decisions made in the work domain for families with special needs. The present research adds to the small but growing literature examining the interplay between home and work life for families with special needs and demonstrates that this is an important research domain in need of additional conceptual and empirical consideration.