Prospect Of Direct Benefit Research Articles

Protocol for a cohort study of the impact of the COVID-19 pandemic on the rate and incidence of bystander cardiopulmonary resuscitation (CPR) after out-of-hospital cardiac arrest

BackgroundSurvival after out-of-hospital cardiac arrest (OHCA) is dependent on early recognition, early cardiopulmonary resuscitation (CPR) and early defibrillation. The purpose of CPR is to maintain some blood flow until the arrival of the emergency medical services (EMS). Our concern is that the COVID-19 pandemic has had a negative effect on the number of patients who get CPR before EMS arrival. The aim of this study is to compare the incidence of bystander CPR during the pandemic with data from before the pandemic.MethodsThe protocol is for a retrospective cohort study where data from existing registries will be used. All participating registries will share aggregated data from 2017 to 2020, and the study team will compare the results from 2020 to results from 2017 to 2019. Due to the General Data Protection Regulation, each participating registry will check for completeness and plausibility, and perform all aggregation of data locally. In the following analysis different registries will be considered as random samples and analysed by means of a generalized linear mixed effects model with Poisson distribution for the outcome, the population covered as offsets, and different registries as random factors.DiscussionThis study does not present the prospect of direct benefit to the patient, but does provide an opportunity to gain a better understanding of the epidemiology of bystander CPR for OHCA patients during a pandemic. By comparing data during the pandemic with already collected information in established registries we believe we can gain valuable information about changes in public response to out-of-hospital cardiac arrest.

Giving Children a Say without Giving Them a Choice: Obtaining Affirmation of a child's Non-dissent to Participation in Nonbeneficial Research.

To what extent, if any, should minors have a say about whether they participate in research that offers them no prospect of direct benefit? This article addresses this question as it pertains to minors who cannot understand enough about what their participation would involve to make an autonomous choice, but can comprehend enough to have and express opinions about participating. The first aim is to defend David Wendler and Seema Shah's claim that minors who meet this description should not be offered a choice about whether they participate. The second aim is to show, contra Wendler and Shah, that the principle of nonmaleficence requires more with respect to giving these minors a say than merely respecting their dissent. Additionally, it requires that investigators obtain affirmation of their non-dissent. This addresses intuitive concerns about denying children a choice, while steering clear of the problems that arise with allowing them one.

Defining the Boundaries of a Right to Adequate Protection: A New Lens on Pediatric Research Ethics.

We argue that the current ethical and regulatory framework for permissible risk levels in pediatric research can be helpfully understood in terms of children's moral right to adequate protection from harm. Our analysis provides a rationale for what we propose as the highest level of permissible risk in pediatric research without the prospect of direct benefit: what we call "relatively minor" risk. We clarify the justification behind the usual standards of "minimal risk" and "a minor increase over minimal risk" and explain why it is permissible to impose any risks at all on child participants who do not stand to benefit directly from enrollment in research. Finally, we illuminate some aspects of the concept of "best interests."

Informed consent to HIV cure research

Trials with highly unfavourable risk–benefit ratios for participants, like HIV cure trials, raise questions about the quality of the consent of research participants. Why, it may be asked, would a...

Research Exceptionalism?: New Ways of Thinking about the Old Problem of Minimal Risk Research with Children

The ethics of research with children that has no prospect of direct benefit to the child research participants is reasonably well settled in practice, but lacks a fully satisfactory account to justify current practices. The difficulty lies in two matters: (i) the way the supposed solution is framed as the equivalent of informed consent in competent, mature adults; and (ii) in the often unstated assumption that the decisions parents make in other settings are not comparable in their moral complexities with decisions whether to enrol children in research that poses little risk to them but may benefit others significantly. I will call this “research exceptionalism” and argue that it has been an impediment to thinking insightfully about minimal risk research with children.

Research consent from young people in resource-poor settings

Authoritative international guidelines stipulate that for minors to participate in research, consent must be obtained from their parents or guardians. Significant numbers of mature minors, particularly in low-income settings, are...

The presumption of benefit in clinical research with children and adolescents

The concept of benefit is integral to the conduct of child and adolescent clinical research. When evaluating the ethical acceptability of research protocols, Institutional Review Boards (IRBs) must determine if benefits of the proposed study outweigh the risks and whether the research offers the prospect for direct benefit. This latter consideration is a particularly crucial determinant in situations where the child or adolescent wishes to dissent to research participation, since parents may legally overrule a dissenting child and compel their participation in research only when the IRB has concluded that the study offers the prospect for direct benefit [1]. Direct benefit refers to research where the purpose is to establish efficacy for an actual treatment for a disease, disorder or problem behavior [2]. King distinguishes other types of benefits that are ancillary to the primary purpose of the research, such as medical procedures or diagnostic tests, medical care, relationships with healthcare providers, positive feelings associated with altruistic behavior and financial compensation as ‘collateral benefits’ [2]. Future benefits to society are further classified as ‘aspirational’. However, a survey of IRB chairs responsible for reviewing research involving children revealed that direct and collateral benefits are often conflated. For example, the availability of psychological counseling unrelated to the research purpose was considered a direct benefit by 60% of the IRB Chair respondents and medical evaluations unrelated to the research purpose were thought to offer the prospect of direct benefit by 51% of the IRB Chairpersons sampled [3]. IRB Chair responses raise the concern that research involving children may be inappropriately perceived as offering direct benefit that, in turn, can curtail the autonomy of children and adolescents to dissent. Researchers and IRBs need a clear definition and conceptual understanding of research benefits, and how prospective research participants may be inclined to perceive them and be influenced by them.

WHICH BENEFITS OF RESEARCH PARTICIPATION COUNT AS ‘DIRECT’?

It is widely held that individuals who are unable to provide informed consent should be enrolled in clinical research only when the risks are low, or the research offers them the prospect of direct benefit. There is now a rich literature on when the risks of clinical research are low enough to enroll individuals who cannot consent. Much less attention has focused on which benefits of research participation count as 'direct', and the few existing accounts disagree over how this crucial concept should be defined. This disagreement raises concern over whether those who cannot consent, including children and adults with severe dementia, are being adequately protected. The present paper attempts to address this concern by considering first what additional protections are needed for these vulnerable individuals. This analysis suggests that the extant definitions of direct benefits either provide insufficient protection for research subjects or pose excessive obstacles to appropriate research. This analysis also points to a modified definition of direct benefits with the potential to avoid these two extremes, protecting individuals who cannot consent without blocking appropriate research.

Regulatory and ethical issues for phase I in utero gene transfer studies.

Clinical gene transfer research has involved adult and child subjects, and it is expected that gene transfer in fetal subjects will occur in the future. Some genetic diseases have serious adverse effects on the fetus before birth, and there is hope that prenatal gene therapy could prevent such disease progression. Research in animal models of prenatal gene transfer is actively being pursued. The prospect of human phase I in utero gene transfer studies raises important regulatory and ethical issues. One issue not previously addressed arises in applying U.S. research regulations to such studies. Specifically, current regulations state that research involving greater than minimal risk to the fetus and no prospect of direct benefit to the fetus or pregnant woman is not permitted. Phase I studies will involve interventions such as needle insertions through the uterus, which carry risks to the fetus including spontaneous abortion and preterm birth. It is possible that these risks will be regarded as exceeding minimal. Also, some regard the probability of therapeutic benefit in phase I studies to be so low that these studies do not satisfy the regulatory requirement that they "hold out the prospect of direct benefit" to subjects. On the basis of these considerations, investigators and institutional review boards might reasonably conclude that some phase I in utero studies are not to be permitted. This paper identifies considerations that are relevant to such judgments and explores ethically acceptable ways in which phase I studies can be designed so that they are permitted by the regulations.

Ethical Considerations About Observational Research in Children

Observational research includes a subset of the broad range of benefits and risks in pediatric research. The exclusive, direct benefit of observational research is the generation of scientific knowledge. This benefit allows for easier communication with families by avoiding the misunderstanding that their child will directly benefit. However, pediatric research that does not offer a prospect of direct benefit can only have limited risks in accordance with the US regulations. The risks of observational research relate to any adverse effects from the disclosure of information from: 1) personally identifiable health information, 2) questionnaires and interviews about health related experiences and 3) data from biological samples for genetic and molecular studies. Whether these privacy and confidentiality risks exceed a "minor increase" over minimal risk, depends on the likelihood that confidentiality will be breached, the likelihood that the breach will result in harm, and the magnitude of the harm. Efforts like database encryption and linked codes can minimize these risks. These issues become more complicated when information has sufficient clinical value to warrant direct disclosure to the family. It is important to communicate basic information to parents about such risks when obtaining parental permission. Further, obtaining consent from adults who have participated in pediatric observational research shows respect for their participation and can facilitate trust. However, if such adults can not be located, when the research has sufficient social value, continual use of the data for ongoing analysis is appropriate.

The participation of children in nontherapeutic diabetes research in the US

Enrollment of children in clinical trials raises many ethical and regulatory issues, particularly when there is no prospect of direct benefit to the participant. The author of this Viewpoint discusses the US federal regulatory guidelines and asks whether they offer appropriate access and protection for all participants in pediatric diabetes research.

Children in medical research: access versus protection

I. ACCESS VERSUS PROTECTION 1. From 1966 to 2005: Balancing Protection and Access in Pediatric Research 2. Access versus Protection: Minority Representation in Pediatric Research II. CHALLENGES TO THE REGULATIONS 3. Overview of the Common Rule and Subpart D 4. Should We Provide Healthy Children with Greater Protection in Medical Research? 5. Informed Consent in Pediatric Research 6. Phase I Research and the Meaning of 'Prospect of Direct Benefit' III. STRENGTHS AND LIMITS OF CURRENT REGULATIONS 7. Human Subjects Protections in Published Pediatric Research 8. Payment in Pediatric Research 9. Research in Schools IV. CASE STUDIES 10. Minimizing Risks: Diabetes Research in Newborns 11. Diabetes Prediction and Prevention Research in Childhood 12. Lead Abatement Research 13. Clinical Asthma Trials 14. Research Not Otherwise Approvable: A Look at One Protocol 15. Evolution of the 407 Process Epilogue

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) 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.

Pediatric Research Posing a Minor Increase Over Minimal Risk and No Prospect of Direct Benefit: Challenging 45 CFR 46.406

Subpart D of the Common Rule establishes 4 categories of research that may be conducted on children. One category, 45 CFR 46.406, permits research posing a minor increase over minimal risk and no prospect of direct benefit but expected to yield vital knowledge about the subjects' disorder or condition. To include other children in research posing a minor increase over minimal risk and no prospect of direct benefit requires federal review and approval of the Secretary of Health and Human Services under 45 CFR 46.407. It is widely held that children generally should not be exposed to more than minimal risk in research without the prospect of direct benefit. To justify deviating from this norm, as 406 allows, two claims must be true: (1) When there is vital knowledge to be gained from studying children, it is permissible to expose some children to a minor increase over minimal risk with no prospect of direct benefit; (2) It is permissible for locally reviewed and approved research to expose only children with the disorder or condition under investigation to greater risk with no prospect of direct benefit. The justification for (1) appears to be grounded in the magnitude of benefit to society combined with the need to study children. This article demonstrates that, even if the necessity and magnitude of benefit to society justify exposing children to increased risk, the decision to categorically restrict participation in such research to children with the disorder or condition under investigation (unless the study is federally reviewed and approved) is not justified. Subpart D should be revised.

Quantifying the Federal Minimal Risk Standard: Implications for Pediatric Research Without a Prospect of Direct Benefit

Quantifying the Federal Minimal Risk Standard: Implications for Pediatric Research Without a Prospect of Direct Benefit

Issues in Oocyte Donation for Stem Cell Research

Stem cell research on human embryonic stem cells derived through use of oocytes originally obtained specifically for research and not for reproductive or medical purposes creates a new class of research subject. In this Policy Forum, the authors explore the ethical issues for those who perform such studies and for research donors. Healthy oocyte donors differ from traditional research subjects in that neither they nor their tissues are the direct objects of study but their tissues are used to create materials for research. Yet they are exposed to significant risks and have no prospect of direct benefit. Researchers in the U.S. who conduct such studies in other countries should follow U.S. guidelines such as those recently released by the National Research Council-Institute of Medicine, even if they are not required by law, because of the special ethical considerations raised by this new category of research subject. The informed consent process for donors should not minimize the risks of oocyte procurement just because the donors are not giving their oocytes for reproductive purposes, or portray stem cell transplantation research as an existing therapy.

Ethical considerations in psychopharmacological research involving children and adolescents.

Increased community utilization of psychotropic medications among children has brought attention to pediatric psychopharmacology research and associated ethical issues. To discuss ethical aspects of child participation in psychopharmacology protocols. Selective review of relevant scientific and regulatory literature. Efficacy and safety of psychotropics in children cannot be entirely inferred from adult data and direct participation of children in research is necessary. Child research must follow special regulations that are in addition to those common to all human research. For research with prospect of direct benefit, a critical factor is whether the risk/benefit ratio is favorable to the participating child. For research without such a prospect, the concepts of minimal risk and minor increase over minimal risk apply. However, the interpretation and application of these principles to specific protocols vary across settings and among ethics committees. Thus far, little empirical investigation has been conducted on children and parents' motivation for research participation, effectiveness of the informed consent and assent procedures, possibility of persistent consequences of exposure to experimental treatments and placebo, and validation of the concepts of minimal risk and minor increase over minimal risk. Research on human subject issues relevant to child participation is a promising approach to improving ethical methods and procedures of pediatric psychopharmacology.

Ethical aspects of research into the etiology of autism.

Advances in understanding autism and other developmental neuropsychiatric disorders will come from an integration of various research strategies including phenomenologic, functional neuroimaging, and pharmacologic methods, as well as epidemiologic approaches aimed at identifying genetic and environmental risk factors. The highly heritable nature of autism makes it scientifically valuable to involve parents and siblings as research participants. However, many studies on autism pose ethical challenges because they do not offer the prospect of direct benefit to subjects. In this article, we present an in-depth ethical analysis of current nontherapeutic research strategies that are common in autism research. The ethical analysis applies a proposed ethical framework for evaluating clinical research focusing on seven ethical requirements: (1) social or scientific value, (2) scientific validity, (3) fair subject selection, (4) favorable risk-benefit ratio, (5) independent review, (6) informed consent, and (7) respect for potential and enrolled research participants.

Children as Research Subjects: Ethical and Legal Considerations

The ethics and regulation of clinical research are grounded in three basic ethical principles: respect for persons, beneficence, and justice. Ethical codes and regulations consist of rules or norms designed to interpret the requirements of these three principles in the specific context of research involving human subjects. Children are regarded as vulnerable subjects by reason of their lack of capacity or competence to give informed consent. Accordingly, as a general rule the regulations require that children not be involved as research subjects unless their parents or guardians give permission. Obtaining the assent of those children who are capable of knowledgeable agreements is also required. Special justifications are required for the involvement of children in research projects in which greater than minimal risk is presented by procedures or interventions that do not hold out the prospect of direct benefit.