Reopening schools safely in the face of COVID-19: Can cluster randomized trials help?

The COVID-19 pandemic has highlighted the challenges of evidence-based health policymaking, as critical precautionary decisions, such as school closures, had to be made urgently on the basis of little evidence. As primary and secondary schools once again close in the face of surging infections, there is an opportunity to rigorously study their reopening. School-aged children appear to be less affected by COVID-19 than adults, yet schools may drive community transmission of the virus. Given the impact of school closures on both education and the economy, schools cannot remain closed indefinitely. But when and how can they be reopened safely? We argue that a cluster randomized trial is a rigorous and ethical way to resolve these uncertainties. We discuss key scientific, ethical, and resource considerations both to inform trial design of school reopenings and to prompt discussion of the merits and feasibility of conducting such a trial.

The right to withdraw from controlled human infection studies: Justifications and avoidance.

The right to withdraw from research without penalty is well established around the world. However, it has been challenged in some corners of bioethics based on concerns about various harms-to participants, to scientific integrity, and to research bystanders-that may stem from withdrawal. These concerns have become particularly salient in emerging debates about the ethics of controlled human infection (CHI) studies in which participants are intentionally infected with pathogens, often in inpatient settings with extensive follow-up. In this article, I provide support for preserving the right to withdraw from research without penalty and demonstrate that it is also typically justified in the specific context of CHI studies. The right is well aligned with individual freedoms outside the research setting, where autonomous individuals are permitted to engage in behaviors that will foreseeably cause them harm; where they cannot be compelled to satisfy contracts for their services, nor penalized for failure to do so; and where their behavior is not constrained by public health authorities except in extreme circumstances. These freedoms are supported by U.S. law, as well as by ethical analysis that is more globally relevant. The problems associated with the right to withdraw, however, remain. The best approach to addressing them is not to restrict the right but rather to avoid initiating research when withdrawal would be especially problematic. If research proceeds, steps can still be taken to minimize participant withdrawal without infringing the right. Investigators can avoid participant surprise through informed consent focused on a study's most burdensome aspects and promote study completion through financial incentives. Should participants nonetheless seek to withdraw, investigators may attempt to persuade them not to do so by encouraging consideration of the range of potential harms that may result. Researchers conducting CHI studies and other research from which withdrawal might be especially problematic should prepare for the possibility of participant withdrawal, respect participant requests to withdraw without penalty, and incorporate various measures to avoid such requests.

Minimal or reasonable? Considering the ethical threshold for research risks to nonconsenting bystanders and implications for nonconsenting participants.

When research poses risks to non-participant bystanders, it is not always practicable to obtain their consent. One approach to assessing how much research risk may be imposed on nonconsenting bystanders is to examine analogous circumstances, including risk thresholds deemed acceptable for nonconsenting research participants and for nonconsensual risks imposed outside the research setting. For nonconsenting participants, US research regulations typically limit risks to those deemed to be "minimal." Outside the research context, US tort law tolerates a more flexible "reasonable" risk threshold. This article advances a preliminary case that nonconsenting participants and nonconsenting bystanders exposed to similar research risks may be entitled to the same level of protection, but that risks generated by research may not be special in kind. Thus, limiting research risks to those that are "reasonable," rather than demanding that they be held to the "minimal" standard, may be the best approach for both nonconsenting participants and nonconsenting bystanders. Further work is needed to establish whether the descriptive standards used to support the analogies relied on here are normatively justifiable, as well as the extent to which the minimal risk standard and the reasonable risk standard would lead to meaningfully different outcomes in practice.

The role of community engagement in addressing bystander risks in research: The case of a Zika virus controlled human infection study.

There is limited guidance on how to assess the ethical acceptability of research risks that extend beyond research participants to third parties (or "research bystanders"). Community or stakeholder engagement has been proposed as one way to address potential harms to community members, including bystanders. Despite widespread agreement on the importance of community engagement in biomedical research, this umbrella term includes many different goals and approaches, agreement on which is ethically required or recommended for a particular context. We analyse the case of a potential Zika virus human challenge trial to assess whether and how community engagement can help promote the ethical acceptability of research posing risks to bystanders. We conclude that, in addition to having intrinsic value, community engagement can improve the identification of bystander risks, effective approaches to minimizing them, and transparency about bystander risks for host communities.

Making the case for completion bonuses in clinical trials.

Attrition is a serious problem in many clinical trials. The practice of offering completion bonuses-financial incentives offered to participants on the condition that they remain in a trial until they reach a prespecified study endpoint-is one means of addressing attrition. Despite their practical appeal, however, completion bonuses remain ethically controversial due to concern that they will coerce or unduly influence participants to not exercise their right to withdraw from a trial. Although this interaction with the right to withdraw does render completion bonuses conceptually distinct from other incentive payments offered to research participants, we argue here that completion bonuses are never coercive and, in the context of effective institutional review board oversight, are unlikely to be unduly influential. Nonetheless, because completion bonuses may in some cases still encourage unreasonable continued participation in a study, additional safeguards are appropriate. Rejecting completion bonuses entirely is, however, unnecessary and would problematically fail to address the significant ethical problems associated with participant attrition.

Differential payment to research participants in the same study: an ethical analysis.

Recognising that offers of payment to research participants can serve various purposes-reimbursement, compensation and incentive-helps uncover differences between participants, which can justify differential payment of participants within the same study. Participants with different study-related expenses will need different amounts of reimbursement to be restored to their preparticipation financial baseline. Differential compensation can be acceptable when some research participants commit more time or assume greater burdens than others, or if inter-site differences affect the value of compensation. Finally, it may be permissible to offer differential incentive payments if necessary to advance the goals of a study. We encourage investigators and Institutional Review Boards to think about whether to offer payment, in what amounts and for what purpose, and also to consider whether differential payment can help promote the scientific and ethical goals of clinical research.

The FDA in the Crosshairs-Science, Politics, and Abortion.

In this Viewpoint, the Supreme Court case FDA v AHM is used to illustrate the tension the FDA faces between science and politics, and state authority over abortion vs federal authority over which drugs may be marketed nationwide.

The Ethics of Expanded Access Research.

This Viewpoint discusses the benefits of expanded access research, the usefulness of expanded access data, the issues surrounding cost and transparency, and the adjusted role of institutional review boards.

Responding to the Call to Meaningfully Assess Institutional Review Board Effectiveness.

This Viewpoint discusses the difficult task of creating a stakeholder-driven, evidence-based approach to assessing institutional review board effectiveness beyond regulatory compliance.

Paying Research Participants: Regulatory Uncertainty, Conceptual Confusion, and a Path Forward.

The practice of offering payment to individuals in exchange for their participation in clinical research is widespread and longstanding. Nevertheless, such payment remains the source of substantial debate, in particular about whether or the extent to which offers of payment coerce and/or unduly induce individuals to participate. Yet, the various laws, regulations, and ethical guidelines that govern the conduct of human subjects research offer relatively little in the way of specific guidance regarding what makes a payment offer ethically acceptable-or not. Moreover, there is a lack of definitional agreement regarding what the terms coercion and undue inducement mean in the human subjects research context. It is, therefore, unsurprising that investigators and Institutional Review Boards (IRBs) experience confusion about how to evaluate offers of payment, and lean toward conservative approaches. These trends are exemplified by our pilot data regarding the ways in which some IRB members and investigators (mis)understand the concepts of coercion and undue inducement, as well as the ways in which certain research institutions oversee offers of payment at a local level. This article systematically examines the legal and ethical dimensions of offering payment to research participants. It argues that many concerns about offers of payment to research participants can be attributed to the misguided view that such offers ought to be treated differently than offers of payment in other contexts, a form of "research exceptionalism." We show that rejection of research exceptionalism with respect to payment helps settle open debates about both how best to define coercion and undue influence, and how to understand the relation between these concepts and offers of payment. We argue for adoption of our preferred definitions, ideally by regulatory authorities, and against the conventional conservatism toward payment of research participants. Instead, we draw attention to the rarely asked, even radical, question: are research participants paid enough? We conclude by arguing that we ought to change the default to favor, rather than encourage suspicion of, offers of payment to research participants.

Preapproval Promises to Voluntarily Withdraw FDA-Approved Drugs.

This Viewpoint provides recommendations for improvements to strengthen legal obligations and decrease ambiguity for the US Food and Drug Administration regarding their reliance on voluntary preapproval withdrawal pledges.

Implementation of an Approach to Equitable Allocation of SARS-CoV-2 Monoclonal Antibodies for Preexposure Prophylaxis: Experience From a Single Medical Center.

Background: During the COVID-19 pandemic, SARS-CoV-2 monoclonal antibodies for preexposure prophylaxis (SMA-PrEP) offered patients who were immunocompromised another option for protection. However, SMA-PrEP posed administrative, operational, and ethical challenges for health care facilities, resulting in few patients receiving them. Although the first SMA-PrEP medication, tixagevimab and cilgavimab, had its authorization revoked due to compromised in vitro efficacy, new SMA-PrEP medications are currently completing clinical trials. This article provides an operational framework for administrative organization, patient identification and prioritization, equitable medication allocation, medication ordering and administration, and patient tracking. Methods: A retrospective cohort study evaluating our hospital's SMA-PrEP administration strategy was performed. Multivariable logistic regression was used to examine factors associated with receipt of SMA-PrEP. Results: Despite the barriers in administering this medication and the scarcity of resources, our hospital was able to administer at least 1 dose of SMA-PrEP to 1359 of 5902 (23.0%) eligible patients. Even with the steps taken to promote equitable allocation, multivariable logistic regression demonstrated that there were still differences by race, ethnicity, and socioeconomic status. As compared with patients who identified as Black, patients who identified as White (odds ratio [OR], 1.85; 95% CI, 1.46-2.33), Asian (OR, 1.59; 95% CI, 1.03-2.46), and Hispanic (OR, 1.53; 95% CI, 1.02-2.44) were more likely to receive SMA-PrEP. When compared with patients with low socioeconomic status, patients with high socioeconomic status (OR, 1.37; 95% CI, 1.05-1.78) were more likely to be allocated SMA-PrEP. Conclusions: Despite efforts to mitigate health care disparities, differences by race/ethnicity and socioeconomic status still arose in patients receiving SMA-PrEP.

How Do Accredited Organizations Evaluate the Quality and Effectiveness of Their Human Research Protection Programs?

BACKGROUND: Meaningfully evaluating the quality of institutional review boards (IRBs) and human research protection programs (HRPPs) is a long-recognized challenge. To be accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP), organizations must demonstrate that they measure and improve HRPP "quality, effectiveness, and efficiency" (QEE). We sought to learn how AAHRPP-accredited organizations interpret and satisfy this standard, in order to assess strengths, weaknesses, and gaps in current approaches and to inform recommendations for improvement. METHODS: We conducted 3 small-group interviews with a total of 19 participant representatives of accredited organizations at the 2019 AAHRPP annual meeting. Participants were eligible if they had familiarity with their organization's approach to satisfying the relevant QEE standard. RESULTS: Participants reported lacking clear definitions for HRPP quality or effectiveness but described various approaches to assessing QEE, typically focused on turnaround time, compliance, and researcher satisfaction. Evaluation of IRB members was described as relatively superficial and information regarding research subject experience was not reported as central to QEE assessment, although participants described several efforts to improve consideration of patient, subject, and community perspectives in IRB review. Participants also described efforts to educate and build relationships with key stakeholders as important features of a high-quality HRPP. While generally satisfied with their approaches, participants expressed concern about resource and time constraints that pushed them to be reactive and automatic about QEE, rather than proactive and critical. CONCLUSIONS: The relevant AAHRPP accreditation standard may obscure critical gaps in defining and measuring QEE elements. We recommend that AAHRPP: (1) offer a definition of QEE or require accredited organizations to provide their own, to help clarify the rationale and goals behind assessment and improvement efforts, and (2) require accredited organizations to establish QEE objectives and measures focused on participant outcomes and deliberative quality during protocol review.