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A growing literature has explored the ethical obligations and current practices related to sharing aggregate results with research participants. However, no prior work has examined these issues in the context of pragmatic clinical trials. Several characteristics of pragmatic clinical trials may complicate both the ethics and the logistics of sharing aggregate results. Among these characteristics include that pragmatic clinical trials may affect the rights, welfare, and interests of not only patient-subjects but also clinicians, meaning that results may be owed to a broader range of groups than typically considered in other research contexts. In addition, some pragmatic clinical trials are conducted under a waiver of informed consent, meaning sharing results may alert participants that they were enrolled without their consent. This article explores the ethical dimensions that can inform decision-making about sharing aggregate results from pragmatic clinical trials, and provides recommendations for that sharing. A central insight is that healthcare institutions-as key partners for the conduct of pragmatic clinical trials-must also be key partners in decision-making about sharing aggregate pragmatic clinical trial results. We conclude with insights for future research., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The literature on the ethics of conscientious objection focuses on objections to participating in morally contested practices. This literature emphasizes the potential for participation to undermine objecting clinicians' moral integrity. Significantly less attention has been given to conscientious objection to teaching morally contested practices. Thus, it is unclear whether teaching morally contested practices has the potential to undermine objecting educators' moral integrity, and to the extent that it does, what steps can be taken to address this concern. We accordingly examine the ethics of conscientious objection to teaching morally contested practices, with a focus on teaching physician-assisted death (PAD) to trainees in US palliative care programs. We focus on three primary components of teaching PAD: (1) teaching the history and context of PAD; (2) teaching trainees how to understand and respond to requests for PAD; and (3) teaching trainees how to provide PAD. We argue that teaching components one and two has little potential to undermine objecting educators' moral integrity. Moreover, permitting objecting educators to opt out of teaching components one and two might undermine the education of trainees. In contrast, allowing objecting educators to opt out of teaching how to provide PAD may be important to preserving their moral integrity, and is unlikely to undermine trainees' education. We argue that educators should be permitted to opt out of teaching trainees how to provide PAD and describe policies that training programs can adopt to implement this approach., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

There has been a good deal of discussion in the literature regarding which subjects are vulnerable in the context of clinical trials. There has been significantly less discussion regarding when and how to include vulnerable subjects in clinical trials. This lack of guidance is a particular problem for trials covered by the US regulations, which mandate strict requirements on the inclusion of three groups: pregnant women/fetuses, prisoners, and children. For the past 30 years, funders, investigators, and institutional review boards have frequently responded to these regulations by excluding pregnant women/fetuses, prisoners, and children from clinical trials. More recent work has emphasized the extent to which a default of exclusion can undermine the value of clinical trials, especially pragmatic trials. A default of exclusion also has the potential to undermine the interests of vulnerable groups, in both the short and the long term. These concerns raise the need for guidance on how to satisfy existing US regulations, while minimizing their negative impact on the value of clinical trials and the interests of vulnerable groups. The present manuscript thus describes a six-step decision procedure that institutional review boards can use to determine when and how to include vulnerable subjects in clinical trials, including pragmatic trials, that are covered by US regulations.

Background: There has been debate about the role of consent in pragmatic trials comparing qualitatively similar interventions. Consent preferences may differ in acute care contexts, given severe illness, time constraints, and other barriers to consent. In addition, studies have not assessed the impact of disclosing financial considerations as a justification for trials. This study was designed to assess preferences of the general public regarding consent for a pragmatic trial in ST-elevation myocardial infarction., Methods: This survey was completed using an online, probability-based panel representative of the US population. It incorporated a randomized, experimental (2 × 2) design assessing (1) preference for written consent versus an alternative (notification after enrollment or brief verbal consent) and (2) impact of including cost as a motivating factor for the trial. The survey used a scenario based on a recent pragmatic trial in ST-elevation myocardial infarction. Primary independent variables were personal preference and recommendation as a member of a review board regarding written consent versus the assigned alternative strategy and personal attitude toward trial enrollment. Descriptive analyses were conducted using post-stratification weights. Regression models were created to examine relationships between demographic variables and consent preference and willingness to enroll. Provision of cost information was incorporated into a regression model to examine its impact on consent preference., Results: The study included 2027 participants. Of those participants, 51.1% versus 45.8% stated a personal preference for written consent versus notification after enrollment; however, 60.0% versus 35.5% preferred brief verbal consent to written consent. Even among respondents stating they would be unlikely to enroll in the trial if asked, more respondents (50.6%) preferred brief verbal consent. The preference for verbal consent was generally shared across demographic categories, although lower educational attainment was associated with reduced acceptance (p = 0.001 for trend). Respondents were more likely to support an alternative to written consent when asked their personal preference than when asked their recommendation as a member of a review board. The provision of cost information did not have a meaningful effect on consent preferences, attitudes toward enrollment, or views about the study., Conclusion: Respondents generally supported prospective involvement in enrollment decisions in the setting of acute myocardial infarction and were particularly supportive of brief verbal consent. This support persisted across demographic categories. The finding that individuals were more likely to support alternatives to written consent when asked for a personal preference rather than as a "committee member" suggests that conservative institutional approaches to consent could hinder implementation of more patient-centered approaches. The role of cost transparency in consent discussions warrants further study.

The most suitable donor for younger patients who undergo hematopoietic stem cell transplantation in the research setting is frequently a minor sibling. These cases raise the question of whether minors who serve as stem cell donors for research subjects should be regarded as research subjects themselves. Regarding pediatric donors as research subjects ensures that an Institutional Review Boards reviews their involvement and determines whether it is appropriate. Yet, Institutional Review Boards must follow the US regulations for pediatric research, which were designed for patients and healthy volunteers, not for healthy donors. As a result, regarding pediatric donors as research subjects also can pose unnecessary obstacles to appropriate and potentially life-saving research. This article considers a new way to address this dilemma. The federal research regulations allow for waiver of some or all of the included requirements when they are unnecessary for a study or a class of studies. We argue that this option offers a way to ensure that the involvement of pediatric donors receives sufficient review and approval without inadvertently undermining valuable and potentially life-saving research., (© The Author(s) 2016.)

Background/aims: Tragedies suggest that phase I trials in healthy participants may be highly risky. This possibility raises concern that phase I trials may exploit healthy participants to develop new therapies, making the translation of scientific discoveries ethically worrisome. Yet, few systematic data evaluate this concern. This article systematically reviews the risks of published phase I trials in healthy participants and evaluates trial features associated with increased risks., Methods: Data on adverse events and trial characteristics were extracted from all phase I trials published in PubMed, Embase, Cochrane, Scopus, and PsycINFO (1 January 2008-1 October 2012). Inclusion criteria were phase I studies that enrolled healthy participants of any age, provided quantitative adverse event data, and documented the number of participants enrolled. Exclusion criteria included (1) adverse event data not in English, (2) a "challenge" study in which participants were administered a pathogen, and (3) no quantitative information about serious adverse events. Data on the incidence of adverse events, duration of adverse event monitoring, trial agent tested, participant demographics, and trial location were extracted., Results: In 475 trials enrolling 27,185 participants, there was a median of zero serious adverse events (interquartile range = 0-0) and a median of zero severe adverse events (interquartile range = 0-0) per 1000 treatment group participants/day of monitoring. The rate of mild and moderate adverse events was a median of 1147.19 per 1000 participants (interquartile range = 651.52-1730.9) and 46.07 per 1000 participants/adverse event monitoring day (interquartile range = 17.80-77.19)., Conclusion: We conclude that phase I trials do cause mild and moderate harms but pose low risks of severe harm. To ensure that this conclusion also applies to unpublished trials, it is important to increase trial transparency., (© The Author(s) 2015.)

Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule (45 CFR 46, Subpart A) and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes "minimal risk," there are important practical implications: the institutional review board may then allow a waiver or alteration of the informed consent process; the study may be carried out in certain vulnerable populations; or the study may be reviewed by institutional review boards using an expedited process. However, it is unclear how institutional review boards should assess the risk levels of pragmatic clinical trials. Such trials typically compare existing, widely used medical therapies or interventions in the setting of routine clinical practice. Some of the therapies may be considered risky of themselves but the study comparing them may or may not add to that pre-existing level of risk. In this article, we examine the common interpretations of research regulations regarding minimal-risk classifications and suggest that they are marked by a high degree of variability and confusion, which in turn may ultimately harm patients by delaying or hindering potentially beneficial research. We advocate for a clear differentiation between the risks associated with a given therapy and the incremental risk incurred during research evaluating those therapies as a basic principle for evaluating the risk of a pragmatic clinical trial. We then examine two pragmatic clinical trials and consider how various factors including clinical equipoise, practice variation, research methods such as cluster randomization, and patients' perspectives may contribute to current and evolving concepts of minimal-risk determinations, and how this understanding in turn affects the design and conduct of pragmatic clinical trials., (© The Author(s) 2015.)

Background: Accurate and consistent risk assessment is vital for the protection of research participants. Yet, current evaluation of the risks of research interventions often does not take into account the relevant empirical data. This approach raises concern that current practice may not be protecting research participants adequately, or that it may be thwarting acceptable research., Purpose: To propose and evaluate the possibility of creating and maintaining a Research Risk Repository which would make empirical data on the risks of research interventions available to institutional review boards, investigators, funders, and others., Methods: Analysis of the usefulness of a Research Risk Repository and evaluation of whether currently available empirical data are sufficient to establish such a repository., Results: Creation of a Research Risk Repository would provide a vital resource for systematically and accurately evaluating the risks of biomedical research. Realizing this goal requires data that have at least 4 characteristics: (1) trustworthy: to ensure credibility to all stakeholders; (2) robust: to support confident risk determinations; (3) inclusive: to cover all potential harms of the interventions under review; and (4) comprehensive: to determine which factors influence the risks of the interventions under review. Evaluation of existing data reveals that they satisfy these requirements for only a few research interventions and, even in those cases, only to a limited extent. Gaps in the currently available evidence highlight the need for systematic collection and maintenance of data on the risks posed by research interventions., Limitations: Creation and maintenance of a Research Risk Repository would be costly and require regular updating as new data are collected, and new practices and interventions emerge., Conclusions: A Research Risk Repository has the potential to significantly improve the consistency and accuracy of the evaluation of research risks. However, currently available data are generally insufficient for this purpose. Future collection and maintenance of data on the risks posed by research interventions will help to ensure that research participants receive appropriate protection and promote important research consistent with adequate subject protection.