The Social Value Misconception in Clinical Research.

Clinical researchers should help respect the autonomy and promote the well-being of prospective study participants by helping them make voluntary, informed decisions about enrollment. However, participants often exhibit poor understanding of important information about clinical research. Bioethicists have given special attention to "misconceptions" about clinical research that can compromise participants' decision-making, most notably the "therapeutic misconception." These misconceptions typically involve false beliefs about a study's purpose, or risks or potential benefits for participants. In this article, we describe a misconception involving false beliefs about a study's potential benefits for non-participants, or its expected social value. This social value misconception can compromise altruistically motivated participants' decision-making, potentially threatening their autonomy and well-being. We show how the social value misconception raises ethical concerns for inherently low-value research, hyped research, and even ordinary research, and advocate for empirical and normative work to help understand and counteract this misconception's potential negative impacts on participants.

A Personalized Patient Preference Predictor for Substituted Judgments in Healthcare: Technically Feasible and Ethically Desirable.

When making substituted judgments for incapacitated patients, surrogates often struggle to guess what the patient would want if they had capacity. Surrogates may also agonize over having the (sole) responsibility of making such a determination. To address such concerns, a Patient Preference Predictor (PPP) has been proposed that would use an algorithm to infer the treatment preferences of individual patients from population-level data about the known preferences of people with similar demographic characteristics. However, critics have suggested that even if such a PPP were more accurate, on average, than human surrogates in identifying patient preferences, the proposed algorithm would nevertheless fail to respect the patient's (former) autonomy since it draws on the 'wrong' kind of data: namely, data that are not specific to the individual patient and which therefore may not reflect their actual values, or their reasons for having the preferences they do. Taking such criticisms on board, we here propose a new approach: the Personalized Patient Preference Predictor (P4). The P4 is based on recent advances in machine learning, which allow technologies including large language models to be more cheaply and efficiently 'fine-tuned' on person-specific data. The P4, unlike the PPP, would be able to infer an individual patient's preferences from material (e.g., prior treatment decisions) that is in fact specific to them. Thus, we argue, in addition to being potentially more accurate at the individual level than the previously proposed PPP, the predictions of a P4 would also more directly reflect each patient's own reasons and values. In this article, we review recent discoveries in artificial intelligence research that suggest a P4 is technically feasible, and argue that, if it is developed and appropriately deployed, it should assuage some of the main autonomy-based concerns of critics of the original PPP. We then consider various objections to our proposal and offer some tentative replies.

Ethics of Controlled Human Infection Studies With Hepatitis C Virus.

Global elimination of hepatitis C virus (HCV) will be difficult to attain without an effective HCV vaccine. Controlled human infection (CHI) studies with HCV were not considered until recently, when highly effective treatment became available. However, now that successful treatment of a deliberate HCV infection is feasible, it is imperative to evaluate the ethics of establishing a program of HCV CHI research. Here, we evaluate the ethics of studies to develop an HCV CHI model in light of 10 ethical considerations: sufficient social value, reasonable risk-benefit profile, suitable site selection, fair participant selection, robust informed consent, proportionate compensation or payment, context-specific stakeholder engagement, fair and open collaboration, independent review and oversight, and integrated ethics research. We conclude that it can be ethically acceptable to develop an HCV CHI model. Indeed, when done appropriately, developing a model should be a priority on the path toward global elimination of HCV.

The Essential Role of Data and Safety Monitoring Boards (DSMBs) in Ensuring the Ethics of Global Vaccine Trials to Address Coronavirus Disease 2019 (COVID-19O).

Coronavirus disease 2019 (COVID-19) vaccines are being developed and implemented with unprecedented speed. Accordingly, trials considered ethical at their inception may quickly become concerning. We provide recommendations for Data and Safety Monitoring Boards (DSMBs) on monitoring the ethical acceptability of COVID-19 vaccine trials, focusing on placebo-controlled trials in low- and middle-income countries.

Ethical challenges for a new generation of early-phase pediatric gene therapy trials.

After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are currently in development. Many of these GTs target rare pediatric diseases that are severely life-limiting, given a lack of effective treatments. As these GTs enter early-phase clinical trials, specific ethical challenges remain unresolved in three domains: evaluating risks and potential benefits, selecting participants fairly, and engaging with patient communities. Drawing on our experience as clinical investigators, basic scientists, and bioethicists involved in a first-in-human GT trial for an ultrarare pediatric disease, we analyze these ethical challenges and offer points to consider for future GT trials.

Judging the Social Value of Health-Related Research: Current Debate and Open Questions.

On the occasion of the 40th anniversary of the Belmont Report-one of the foundational documents of modern research ethics-this article reviews the ethical debate about the social value of health-related research with human participants. It shows that the Belmont Report discusses the social value of research only cursorily, much like most of the research ethics literature until recently. The article then reviews the current debate and open questions about the social value of health-related research, organized around three questions: (1) is social value a necessary ethical requirement for health-related research with human participants? (2) if so, how should a social value requirement should be specified? and (3) how should such a requirement be implemented in practice?

Judging the social value of controlled human infection studies.

In controlled human infection (CHI) studies, investigators deliberately infect healthy individuals with pathogens in order to study mechanisms of disease or obtain preliminary efficacy data on investigational vaccines and medicines. CHI studies offer a fast and cost-effective way of generating new scientific insights, prioritizing investigational products for clinical testing, and reducing the risk that large numbers of people are exposed to ineffective or harmful substances in research or in practice. Yet depending on the pathogen, CHI studies can involve significant risks or burdens for participants, pose risks to individuals or communities not involved in the research, and lead to public controversy. It is therefore essential to ensure that the risks of CHI studies are justified by their social value-that is, their potential to generate benefits for society-and that public trust can be maintained. In this paper, we aim to clarify how research sponsors, research ethics committees and other reviewers should judge the social value of CHI studies. We develop a list of relevant considerations for making social value judgments based on the standard view of social value. We then use this list to discuss the example of potentially conducting dengue virus CHI studies in endemic settings. We argue that dengue virus CHI studies in endemic settings would fall on the higher end of the spectrum of social value, mostly because of their potential to redirect all fields of future dengue research. Drawing on this discussion, we derive several general recommendations for how reviewers should judge the social value of CHI studies.

Informed consent for controlled human infection studies in low- and middle-income countries: Ethical challenges and proposed solutions.

In controlled human infection studies (CHIs), participants are deliberately exposed to infectious agents in order to better understand the mechanism of infection or disease and test therapies or vaccines. While most CHIs have been conducted in high-income countries, CHIs have recently been expanding into low- and middle-income countries (LMICs). One potential ethical concern about this expansion is the challenge of obtaining the voluntary informed consent of participants, especially those who may not be literate or have limited education. In some CHIs in LMICs, researchers have attempted to address this potential concern by limiting access to literate or educated populations. In this paper, we argue that this practice is unjustified, as it does not increase the chances of obtaining valid informed consent and therefore unfairly excludes illiterate populations and populations with lower education. Instead, we recommend that investigators improve the informed consent process by drawing on existing data on obtaining informed consent in these populations and interventions aimed at improving their understanding. Based on a literature review, we provide concrete suggestions for how to follow this recommendation and ensure that populations with lower literacy or education are given a fair opportunity to protect their rights and interests in the informed consent process.

[Covid-19: An ad hoc public health ethics consultation]. / Covid-19: Eine Ad hoc Public-Health-Ethikberatung.

In this paper we describe the process and content of our ad hoc public health ethics consultation for a Bavarian health authority in relation to Covid-19.

Evaluating the risks of public health programs: Rational antibiotic use and antimicrobial resistance.

Existing ethical frameworks for public health provide insufficient guidance on how to evaluate the risks of public health programs that compromise the best clinical interests of present patients for the benefit of others. Given the relevant similarity of such programs to clinical research, we suggest that insights from the long-standing debate about acceptable risk in clinical research can helpfully inform and guide the evaluation of risks posed by public health programs that compromise patients' best clinical interests. We discuss how lessons learned regarding the ethics of risk in one context can be fruitfully transferred to the other, using the example of a so-called 'rational antibiotic use' guideline that limits antimicrobial prescribing in order to curb antimicrobial resistance.

Affordability and Non-Perfectionism in Moral Action.

One rationale policy-makers sometimes give for declining to fund a service or intervention is on the grounds that it would be 'unaffordable', which is to say, that the total cost of providing the service or intervention for all eligible recipients would exceed the budget limit. But does the mere fact that a service or intervention is unaffordable present a reason not to fund it? Thus far, the philosophical literature has remained largely silent on this issue. However, in this article, we consider this kind of thinking in depth. Albeit with certain important caveats, we argue that the use of affordability criteria in matters of public financing commits what Parfit might have called a 'mistake in moral mathematics'. First, it fails to abide by what we term a principle of 'non-perfectionism' in moral action: the mere fact that it is practically impossible for you to do all the good that you have reason to do does not present a reason not to do whatever good you can do. And second, when used as a means of arbitrating between which services to fund, affordability criteria can lead to a kind of 'numerical discrimination'. Various attendant issues around fairness and lotteries are also discussed.

Choices in vaccine trial design in epidemics of emerging infections.

In a Policy Forum, Marc Lipsitch and colleagues discuss trial design issues in infectious disease outbreaks.

Genetic research on biospecimens poses minimal risk.

Genetic research on human biospecimens is increasingly common. However, debate continues over the level of risk that this research poses to sample donors. Some argue that genetic research on biospecimens poses minimal risk; others argue that it poses greater than minimal risk and therefore needs additional requirements and limitations. This debate raises concern that some donors are not receiving appropriate protection or, conversely, that valuable research is being subject to unnecessary requirements and limitations. The present paper attempts to resolve this debate using the widely-endorsed 'risks of daily life' standard. The three extant versions of this standard all suggest that, with proper measures in place to protect confidentiality, most genetic research on human biospecimens poses minimal risk to donors.

Tackling anti-microbial resistance: ethical framework for rational antibiotic use.

Background: To reduce the effect of antimicrobial resistance and to preserve antibiotic effectiveness, clinical guidelines and health policy documents call for the rational use of antibiotics, which aims to reduce unnecessary or minimally effective antibiotic use. Methods: Through ethical analysis, we show that rational use programmes can lead to ethical conflicts, because they sometimes place patients at risk of harm-for example, a delayed switch to second-line antibiotics for community-acquired pneumonia can lead to substantial increases in mortality. Results: Implementing the rational use of antibiotics can lead to conflicts between promoting patients' clinical interests and preserving antibiotic effectiveness for future use. The resulting ethical dilemma for clinicians, patients and policy makers has so far not been adequately addressed. Conclusions: Existing guidance for acceptable risks in clinical research can help to define risk thresholds for the rational use of antibiotics. We develop an ethical framework that allows clinicians and policy-makers to evaluate policies for rational antibiotic use in six practical steps. This framework can help guide clinical practice and health policy.

Standards of practice in empirical bioethics research: towards a consensus.

BACKGROUND: This paper reports the process and outcome of a consensus finding project, which began with a meeting at the Brocher Foundation in May 2015. The project sought to generate and reach consensus on standards of practice for Empirical Bioethics research. The project involved 16 academics from 5 different European Countries, with a range of disciplinary backgrounds. METHODS: The consensus process used a modified Delphi approach. RESULTS: Consensus was reached on 15 standards of practice, organised into 6 domains of research practice (Aims, Questions, Integration, Conduct of Empirical Work, Conduct of Normative Work; Training & Expertise). CONCLUSIONS: Through articulating these standards we outline a position that encourages responses, and through those responses we will be able to identify points of agreement and contestation that will drive the conversation forward. In that vein, we would encourage researchers, funders and journals to engage with what we have proposed, and respond to us, so that our community of practice of empirical bioethics research can develop and evolve further.

In Defense of a Social Value Requirement for Clinical Research.

Many guidelines and commentators endorse the view that clinical research is ethically acceptable only when it has social value, in the sense of collecting data which might be used to improve health. A version of this social value requirement is included in the Declaration of Helsinki and the Nuremberg Code, and is codified in many national research regulations. At the same time, there have been no systematic analyses of why social value is an ethical requirement for clinical research. Recognizing this gap in the literature, recent articles by Alan Wertheimer and David Resnik argue that the extant justifications for the social value requirement are unpersuasive. Both authors conclude, contrary to almost all current guidelines and regulations, that it can be acceptable across a broad range of cases to conduct clinical research which is known prospectively to have no social value. The present article assesses this conclusion by critically evaluating the ethical and policy considerations relevant to the claim that clinical research must have social value. This analysis supports the standard view that social value is an ethical requirement for the vast majority of clinical research studies and should be mandated by applicable guidelines and policies.

Public Reasoning and Health-Care Priority Setting: The Case of NICE.

Health systems that aim to secure universal patient access through a scheme of prepayments-whether through taxes, social insurance, or a combination of the two-need to make decisions on the scope of coverage that they guarantee: such tasks often falling to a priority-setting agency. This article analyzes the decision-making processes at one such agency in particular-the UK's National Institute for Health and Care Excellence (NICE)-and appraises their ethical justifiability. In particular, we consider the extent to which NICE's model can be justified on the basis of Rawls's conception of "reasonableness." This test shares certain features with the well-known Accountability for Reasonableness (AfR) model but also offers an alternative to it, being concerned with how far the values used by priority-setting agencies such as NICE meet substantive conditions of reasonableness irrespective of their procedural virtues. We find that while there are areas in which NICE's processes may be improved, NICE's overall approach to evaluating health technologies and setting priorities for health-care coverage is a reasonable one, making it an exemplar for other health-care systems facing similar coverage dilemmas. In so doing we offer both a framework for analysing the ethical justifiability of NICE's processes and one that might be used to evaluate others.

Towards Equity in Health: Researchers Take Stock.

For the 2016 end-of-the-year editorial, the PLOS Medicine editors asked 7 global health leaders to discuss developments relevant to the equitable provision of medical care to all populations. The result is a collection of expert views on ethical trial design, research during outbreaks, high-burden infectious diseases, diversity in research and protection of migrants.

Ethical Rationale for the Ebola "Ring Vaccination" Trial Design.

The 2014 Ebola virus epidemic is the largest and most severe ever recorded. With no approved vaccines or specific treatments for Ebola, clinical trials were launched within months of the epidemic in an unprecedented show of global partnership. One of these trials used a highly innovative "ring vaccination" design. The design was chosen for operational, scientific, and ethical reasons--in particular, it was regarded as ethically superior to individually randomized placebo-controlled trials. We scrutinize the ethical rationale for the ring vaccination design. We argue that the ring vaccination design is ethical but fundamentally equivalent to placebo-controlled designs with respect to withholding a potentially effective intervention from the control group. We discuss the implications for the ongoing ring vaccination trial and future research.