IRBs and the Protection-Inclusion Dilemma: Finding a Balance.

Institutional review boards, tasked with facilitating ethical research, are often pulled in competing directions. In what we call the protection-inclusion dilemma, we acknowledge the tensions IRBs face in aiming to both protect potential research participants from harm and include under-represented populations in research. In this manuscript, we examine the history of protectionism that has dominated research ethics oversight in the United States, as well as two responses to such protectionism: inclusion initiatives and critiques of the term vulnerability. We look at what we know about IRB decision-making in relation to protecting and including "vulnerable" groups in research and examine the lack of regulatory guidance related to this dilemma, which encourages protection over inclusion within IRB practice. Finally, we offer recommendations related to how IRBs might strike a better balance between inclusion and protection in research ethics oversight.

Navigating the ethics of remote research data collection.

COVID-19 has accelerated broad trends already in place toward remote research data collection and monitoring. This move implicates novel ethical and regulatory challenges which have not yet received due attention. Existing work is preliminary and does not seek to identify or grapple with the issues in a rigorous and sophisticated way. Here, we provide a framework for identifying and addressing challenges that we believe can help the research community realize the benefits of remote technologies while preserving ethical ideals and public trust. We organize issues into several distinct categories and provide points to consider in a table that can help facilitate ethical design and review of research studies using remote health instruments.

An ethics framework for consolidating and prioritizing COVID-19 clinical trials.

Given the dearth of established safe and effective interventions to respond to COVID-19, there is an urgent ethical imperative to conduct meaningful clinical research. The good news is that interventions to be tested are not in short supply. Unfortunately, the human and material resources needed to conduct these trials are finite. It is essential that trials be robust and meet enrollment targets and that lower-quality studies not be permitted to displace higher-quality studies, delaying answers to critical questions. Yet, with few exceptions, existing research review bodies and processes are not designed to ensure these conditions are satisfied. To meet this challenge, we offer guidance for research institutions about how to ethically consolidate and prioritize COVID-19 clinical trials, while recognizing that consolidation and prioritization should also take place upstream (among manufacturers and funders) and at a higher level (e.g. nationally). In our proposed three-stage process, trials must first meet threshold criteria. Those that do are evaluated in a second stage to determine whether the institution has sufficient capacity to support all proposed trials. If it does not, the third stage entails evaluating studies against two additional sets of comparative prioritization criteria: those specific to the study and those that aim to advance diversification of an institution's research portfolio. To implement these criteria fairly, we propose that research institutions form COVID-19 research prioritization committees. We briefly discuss some important attributes of these committees, drawing on the authors' experiences at our respective institutions. Although we focus on clinical trials of COVID-19 therapeutics, our guidance should prove useful for other kinds of COVID-19 research, as well as non-pandemic research, which can raise similar challenges due to the scarcity of research resources.

Economic vulnerability and payment for research participation.

There has been significant analysis of the ethical and regulatory issues involved with paying research participants, but less attention has been focused specifically on paying economically vulnerable individuals and the unique challenges it may present. This is important, as individuals of lower socio-economic standing are present in all disease groups and study populations. Moreover, clinical research is often conducted in economically under-developed locales, such as lower- or middle-income countries as well as impoverished locales of otherwise wealthy nations (such as, for example, rural Appalachia in the United States). Is it ethical to offer payment in such contexts? What are the ethical considerations relevant for determining payment rates and practices to individuals who are economically vulnerable? We offer an analysis of these issues, focusing on four unique areas of concern: (1) whether the risk of undue influence is greater for economically vulnerable individuals than for wealthier ones; (2) whether payment unacceptably raises the risk of 'unjust influence' or disproportionate representation of poor people in clinical research; (3) the positive reasons in favor of paying economically vulnerable people that stem from the ethical value of fairness; and (4) appropriate compensation rates for economically vulnerable populations. Our analysis supports the position that payment to economically vulnerable populations is ethically justified and indeed desirable when certain conditions are met.

Oversight of Patient-Centered Outcomes Research: Recommendations From a Delphi Panel.

A key aim of patient-centered outcomes research (PCOR) is to generate data that are important to patients by deliberately and extensively involving them in all aspects of research, from design to dissemination. However, certain elements of PCOR raise challenging and potentially novel ethical and regulatory issues for institutional review boards and oversight bodies. These challenges stem primarily from the engagement of patients in roles other than research subject, such as advisors, study personnel, and co-investigators, which gives rise to questions about appropriate levels of protection, training, and education, as well as identifying and managing conflicts of interest. This article presents and discusses recommendations from a Delphi expert panel that was convened to address these and other PCOR-related oversight challenges.

Disclosure of Possible Trial Termination to Participants of Interventional Clinical Trials.

This study evaluates a cross-section of interventional clinical trials registered on ClinicalTrials.gov with publicly available informed consent forms along with the proportion of trials that disclosed the possibility of trial termination.

When clinical trials compete: prioritising study recruitment.

It is not uncommon for multiple clinical trials at the same institution to recruit concurrently from the same patient population. When the relevant pool of patients is limited, as it often is, trials essentially compete for participants. There is evidence that such a competition is a predictor of low study accrual, with increased competition tied to increased recruitment shortfalls. But there is no consensus on what steps, if any, institutions should take to approach this issue. In this article, we argue that an institutional policy that prioritises some trials for recruitment ahead of others is ethically permissible and indeed prima facie preferable to alternative means of addressing recruitment competition. We motivate this view by appeal to the ethical importance of minimising the number of studies that begin but do not complete, thereby exposing their participants to unnecessary risks and burdens in the process. We then argue that a policy of prioritisation can be fair to relevant stakeholders, including participants, investigators and funders. Finally, by way of encouraging and helping to frame future debate, we propose some questions that would need to be addressed when identifying substantive ethical criteria for prioritising between studies.

Using Social Media as a Research Recruitment Tool: Ethical Issues and Recommendations.

The use of social media as a recruitment tool for research with humans is increasing, and likely to continue to grow. Despite this, to date there has been no specific regulatory guidance and there has been little in the bioethics literature to guide investigators and institutional review boards (IRBs) faced with navigating the ethical issues such use raises. We begin to fill this gap by first defending a nonexceptionalist methodology for assessing social media recruitment; second, examining respect for privacy and investigator transparency as key norms governing social media recruitment; and, finally, analyzing three relatively novel aspects of social media recruitment: (i) the ethical significance of compliance with website "terms of use"; (ii) the ethics of recruiting from the online networks of research participants; and (iii) the ethical implications of online communication from and between participants. Two checklists aimed at guiding investigators and IRBs through the ethical issues are included as appendices.

When and Why Is Research without Consent Permissible?

The purpose of consent is to let a person waive her rights of control over some aspects of her life. But becoming part of a research study does not always seriously undermine one's control.

Interactive Media-Based Approach for an Exception From Informed Consent Trial Involving Patients With Trauma.

Importance: Exception From Informed Consent (EFIC) research requires community consultation (CC) and public disclosure (PD). Traditional methods of conducting CC and PD are slow, expensive, and labor intensive. Objective: To describe the feasibility and reach of a novel interactive, media-based approach to CC and PD and to identify the similarities and differences between trial sites in website views, survey responses, online community forum attendance, and opt-out requests. Design, Setting, and Participants: This survey study analyzed the CC and PD campaigns conducted for the TAP trial (Evaluation of BE1116 in Patients With Traumatic Injury and Acute Major Bleeding to Improve Survival), an EFIC trial of the early administration of prothrombin complex concentrate in patients with trauma. The CC and PD campaigns consisted of social media advertisements, linked websites, community surveys, and online community forums. These activities were coordinated from a central site and approved by a central institutional review board. This study focused on the first 52 of 91 TAP trial sites (level I trauma centers) in the US to have completed their CC and PD campaigns. Community members in the catchment areas of the participating trauma centers were targeted. Data analysis was conducted between October 2023 and February 2024. Exposure: Social media advertisements, surveys, and online community meetings conducted as part of the CC and PD campaign for the TAP trial. Main Outcomes and Measures: Social media campaign reach and engagement, web page views, survey results, online community forum attendance, and opt-out requests. Results: Fifty-two trial sites were approved for participant enrollment. Social media advertisements were displayed 92 million times, reaching 11.8 million individuals. The median (IQR) number of people reached in each location was 210 317 (172 068-276 968). Site-specific websites were viewed 144 197 times (median [IQR] viewings per site, 2984 [1267-4038]). A total of 17 206 fully or partly completed surveys were received, and survey respondents had a median (IQR) age of 40.1 (15-65) years and included 10 444 females (60.7%). Overall, 60.6% survey respondents said they would want to be entered into the trial even if they could not give consent, 87.7% agreed that emergency care research was necessary, and 88.0% agreed that the TAP trial should be conducted in their community. Online community forums were attended by a median (IQR) number of 38 (20-63) people. Four opt-out requests were received. Conclusions and Relevance: The interactive media-based approach to CC and PD for the ongoing TAP trial showed the feasibility and benefits of executing an efficient, coordinated, centrally run series of locally branded and geographically targeted CC and PD campaigns for a large EFIC study.

Terms and conditions apply: an ethical analysis of mobile health user agreements in research.

Mobile health (mHealth) technologies raise unique risks to user privacy and confidentiality that are often embedded in lengthy and complex Privacy Policies, Terms of Use, and End User License Agreements. We seek to improve the ethical review of these documents ('user agreements') and their risks in research using mHealth technologies by providing a framework for identifying when these risks are research risks, categorizing the key information in these agreements under relevant ethical and regulatory categories, and proposing strategies to mitigate them. MHealth user agreements typically describe the nature of the data collected by mHealth technologies, why or for what purposes user data are collected and shared, who will have access to the different types of data collected, and may include exculpatory language. The risks raised by data collection and sharing typically increase with the sensitivity and identifiability of the data and vary by whether data are shared with researchers, the technology developer, and/or third-party entities. The most important risk mitigation strategy is disclosure of the key information found in user agreements to participants during the research consent process. In addition, researchers should prioritize mHealth technologies with favorable risk-benefit balances.

Ensuring the Scientific Value and Feasibility of Clinical Trials: A Qualitative Interview Study.

BACKGROUND: Ethical and scientific principles require that clinical trials address an important question and have the resources needed to complete the study. However, there are no clear standards for review that would ensure that these principles are upheld. METHODS: We conducted semi-structured interviews with a convenience sample of nineteen experts in clinical trial design, conduct, and/or oversight to elucidate current practice and identify areas of need with respect to ensuring the scientific value and feasibility of clinical trials prior to initiation and while ongoing. We used a priori and grounded theory to analyze the data and constant comparative method to induce higher order themes. RESULTS: Interviewees perceived determination of scientific value as the responsibility of the investigator and, secondarily, other parties who review or oversee research. Interviewees reported that ongoing trials are rarely reevaluated due to emerging evidence from external sources, evaluation is complex, and there would be value in the development of standards for monitoring and evaluating evidence systematically. Investigators, IRBs, and/or data monitoring committees (DMCs) could undertake these responsibilities. Feasibility assessments are performed but are typically inadequate; potential solutions are unclear. CONCLUSIONS: There are three domains where current approaches are suboptimal and in which further guidance is needed. First, who has the responsibility for conducting scientific review, whether it be the investigator, IRB, and/or DMC is often unclear. Second, the standards for scientific review (e.g., appropriate search terms, data sources, and analytic plan) should be defined. Third, guidance is needed on the evaluation of ongoing studies in light of potentially new and evolving evidence, with particular reference to evidence from outside the trial itself.

Deprioritization of Ongoing Clinical Trials.

To be ethical, clinical trials must exhibit a favorable risk-benefit balance at the time of their initiation. However, in some cases, the expected value of a study decreases while the study is ongoing, due to developments outside of the study itself, such as findings from other studies or an otherwise shifting evidence base. While such situations are acknowledged in the research community, they have not received sufficient attention, given the high costs of uninformative studies, both in material and human capital. In addition, the Covid-19 pandemic has exposed serious shortcomings with current approaches to monitoring studies for continued relevance and value. In this article, with reference to a case study from the Covid-19 pandemic, we identify and describe the importance and challenge of ensuring that clinical trials continue to exhibit scientific relevance and value once initiated. We explore the ethical dynamics of these situations and identify unresolved issues. While more empirical work is needed to ensure that proposed solutions to the issues are evidence based, we offer some provisional considerations that amount to a framework for approaching these challenging situations.

How to limit uninformative trials: Results from a Delphi working group.

To be justifiable, clinical trials must test novel hypotheses and produce informative results. However, many trials fail on this score. A Delphi process was used to establish consensus on 35 recommendations across five domains related to the role of scientific review in preventing uninformative trials.