Algorithmic identification of persons with dementia for research recruitment: ethical considerations.

Underdiagnosis, misdiagnosis, and patterns of social inequality that translate into unequal access to health systems all pose barriers to identifying and recruiting diverse and representative populations into research on Alzheimer's disease and Alzheimer's disease related dementias. In response, some have turned to algorithms to identify patients living with dementia using information that is associated with this condition but that is not as specific as a diagnosis. This paper explains six ethical issues associated with the use of such algorithms including the generation of new, sensitive, identifiable medical information for research purposes without participant consent, issues of justice and equity, risk, and ethical communication. It concludes with a discussion of strategies for addressing these issues and prompting valuable research.

A normative framework for artificial intelligence as a sociotechnical system in healthcare.

Artificial intelligence (AI) tools are of great interest to healthcare organizations for their potential to improve patient care, yet their translation into clinical settings remains inconsistent. One of the reasons for this gap is that good technical performance does not inevitably result in patient benefit. We advocate for a conceptual shift wherein AI tools are seen as components of an intervention ensemble. The intervention ensemble describes the constellation of practices that, together, bring about benefit to patients or health systems. Shifting from a narrow focus on the tool itself toward the intervention ensemble prioritizes a "sociotechnical" vision for translation of AI that values all components of use that support beneficial patient outcomes. The intervention ensemble approach can be used for regulation, institutional oversight, and for AI adopters to responsibly and ethically appraise, evaluate, and use AI tools.

Varieties of Community Uncertainty and Clinical Equipoise.

The judgments of conscientious and informed experts play a central role in two elements of clinical equipoise. The first, and most widely discussed, element involves ensuring that no participant in a randomized trial is allocated to a level of treatment that everyone agrees is substandard. The second, and less often discussed, element involves ensuring that trials are likely to generate social value by producing the information necessary to resolve a clinically meaningful uncertainty or disagreement about the relative merits of a set of interventions. The distribution of judgments in expert communities can take many forms, each with important implications for whether a trial satisfies one or both elements of clinical equipoise. In this article we use a graphical approach to represent three ways in which expert community uncertainty can vary: by spread, modality, and skew. Understanding these different distributions of expert judgment has three important implications: it helps to make operational the requirement of social value, it shows that some conditions for initiating studies to promote social value diverge from common assumptions about clinical equipoise, and it has important implications for how trials should be designed and monitored, and what patients should be told during informed consent.

Artificial intelligence in medicine: Overcoming or recapitulating structural challenges to improving patient care?

There is considerable enthusiasm about the prospect that artificial intelligence (AI) will help to improve the safety and efficacy of health services and the efficiency of health systems. To realize this potential, however, AI systems will have to overcome structural problems in the culture and practice of medicine and the organization of health systems that impact the data from which AI models are built, the environments into which they will be deployed, and the practices and incentives that structure their development. This perspective elaborates on some of these structural challenges and provides recommendations to address potential shortcomings.

A Dilemma for Respecting Autonomy: Bridge Technologies and the Hazards of Sequential Decision-Making.

Respect for patient autonomy can apply at two levels: ensuring that patient care reflects their considered values and wishes and honoring patient preferences about how to make momentous decisions. Caregivers who seek to respect patient autonomy in the context of some end-of-life decisions face a dilemma. Because these decisions are fraught, patients may prefer to approach them sequentially, only making decisions at the time they arise. However, respecting patients' preferences for a sequential approach can increase the likelihood that surrogates and care teams wind up in situations in which they lack information needed to ensure patients receive care that conforms to their considered values after they are no longer competent to make decisions for themselves. Sequential decision-making can thus conflict with the goal of ensuring care reflects the wishes of patients. After illustrating how this dilemma can arise in the use of life-sustaining "bridge" technologies, we argue that care teams may be warranted in requiring patients to articulate their wishes in an advance care plan before treatment begins. In some cases, care teams may even be permitted to refuse to undertake certain courses of care, unless patients articulate their wishes in an advance care plan.

When Can Nonrandomized Studies Support Valid Inference Regarding Effectiveness or Safety of New Medical Treatments?

The randomized controlled trial (RCT) is the gold standard for evaluating the causal effects of medications. Limitations of RCTs have led to increasing interest in using real-world evidence (RWE) to augment RCT evidence and inform decision making on medications. Although RWE can be either randomized or nonrandomized, nonrandomized RWE can capitalize on the recent proliferation of large healthcare databases and can often answer questions that cannot be answered in randomized studies due to resource constraints. However, the results of nonrandomized studies are much more likely to be impacted by confounding bias, and the existence of unmeasured confounders can never be completely ruled out. Furthermore, nonrandomized studies require more complex design considerations which can sometimes result in design-related biases. We discuss questions that can help investigators or evidence consumers evaluate the potential impact of confounding or other biases on their findings: Does the design emulate a hypothetical randomized trial design? Is the comparator or control condition appropriate? Does the primary analysis adjust for measured confounders? Do sensitivity analyses quantify the potential impact of residual confounding? Are methods open to inspection and (if possible) replication? Designing a high-quality nonrandomized study of medications remains challenging and requires broad expertise across a range of disciplines, including relevant clinical areas, epidemiology, and biostatistics. The questions posed in this paper provide a guiding framework for assessing the credibility of nonrandomized RWE and could be applied across many clinical questions.

The Ethics of Research on Treatment Discontinuation.

Discussions of the ethics of research with human participants frequently focus on early-phase studies that investigate the clinical properties of novel interventions,1 randomized controlled trials that investigate the relative diagnostic, prophylactic, or therapeutic merits of promising new interventions,2 or pragmatic research on existing practices.3 There has also been significant discussion of ethical issues in trials that employ a "washout period," in which participants discontinue one treatment before being exposed to another.4.

Ethically designing research to inform multidimensional, rapidly evolving policy decisions: Lessons learned from the PROMISE HIV Perinatal Prevention Trial.

Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study's standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the "PROMISE" (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study's standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.

Solitary death and new lifestyles during and after COVID-19: wearable devices and public health ethics.

BACKGROUND: Solitary death (kodokushi) has recently become recognized as a social issue in Japan. The social isolation of older people leads to death without dignity. With the outbreak of COVID-19, efforts to eliminate solitary death need to be adjusted in line with changes in lifestyle and accompanying changes in social structure. Health monitoring services that utilize wearable devices may contribute to this end. Our goals are to outline how wearable devices might be used to (1) detect emergency situations involving solitary older people and swiftly connect them with medical treatment, to (2) reduce the frequency of deaths that remain undiscovered and (3) to reduce social isolation by promoting social interaction. METHODS: Theoretical and philosophical approaches were adopted to examine ethical issues surrounding the application of wearable devices and cloud-based information processing systems to prevent solitary death in the world with/after COVID-19. MAIN BODY: (1) Technology cannot replace social connections; without social support necessary to foster understanding of the benefits of health management through wearable devices among older adults, such devices may remain unused, or not used properly. (2) Maturity of the technology; systems face the difficult task of detecting and responding to a wide range of health conditions and life-threatening events in time to avert avoidable morbidity and mortality. (3) Autonomy and personhood; promoting the voluntary use of wearable devices that are a part of larger efforts to connect isolated individuals to a community or social services might be effective. Legal force should be avoided if possible. There is some concern that landlords may require an older person to sign a contract agreeing to wear a device. The autonomy of solitary older people should be respected. (4) Governance: policies must be developed to limit access to data from wearables and the purposes for which data can be used. CONCLUSION: If thoughtfully deployed under proper policy constraints, wearable devices offer a way to connect solitary older people to health services and could reduce cases of solitary death while respecting the personhood of the user.

Self-Defeating Codes of Medical Ethics and How to Fix Them: Failures in COVID-19 Response and Beyond.

Statements of the core ethical and professional responsibilities of medical professionals are incomplete in ways that threaten fundamental goals of medicine. First, in the absence of explicit guidance for responding to cases in which there is significant uncertainty or disagreement about the relative therapeutic, prophylactic or diagnostic merits of available interventions they perpetuate self-defeating practices. Second, without addressing the role of advertising in shaping patient and community preferences they risk creating moral loopholes that bypass and undermine professional duties of fidelity, honesty and transparency. In both cases, these flaws are exacerbated by an individualism that ignores the critical role of health systems in managing and reducing uncertainty and conflict over best practices, and in communicating with and shaping the expectations of the public. These points are illustrated with examples from the response to COVID-19 and suggestions for reform are proposed.

Loopholes in the Research Ethics System? Informed Consent Waivers in Cluster Randomized Trials with Individual-Level Intervention.

Individual-cluster trials randomize groups of individuals but deliver study interventions directly to individual participants. We examine three arguments that might justify the perception that the bar for a waiver of consent should be lower in such trials than for individually randomized trials. We contend that if these arguments are treated as sufficient to grant a waiver of consent, then a loophole emerges in research oversight. Such loopholes are morally hazardous for study participants, the integrity of science, and public trust in the research enterprise. We conclude by articulating the standards that research ethics committees should use to evaluate requests for waivers of consent in individual-cluster trials.

Integrating public health programs and research after the malaria vaccine implementation program (MVIP): Recommendations for next steps.

BACKGROUND: In February 2020, international controversy arose about the ethical acceptability of the WHO Malaria Vaccine Implementation Program (MVIP). Whereas some have argued that this program must be seen as research that is not in line with international ethical standards, notably regarding informed consent and local ethical review, some WHO representatives consider the MVIP as a public health implementation program that need not adhere to these standards. METHODS: We performed a case analysis in light of the 2016 CIOMS International Ethical Guidelines for Health-related Research involving Humans. FINDINGS: We argue that the MVIP has a substantial research component, and that it is prudent to therefore apply ethical norms for research involving humans, such as the CIOMS guidelines. Accordingly, we agree that the ethical requirements of informed consent and independent ethical review have not been met. In addition, we are concerned that the study might not meet CIOMS's social value requirement. RECOMMENDATIONS: We urge WHO to release more details about the process that led to the MVIP program and make the MVIP protocol publicly available. The full protocol should be assessed by the relevant ethics committees, new and already enrolled parents should be informed about the uncertainties under investigation and given a real opportunity to consent or refuse (continued) participation, communities should be engaged, and aspects of MVIP that require alteration in light of ethical review should be altered, if possible. Furthermore, in order to improve good ethical practices, it is necessary to engage in international debate regarding the integration of research and public health programs. Procedurally, vaccine implementation programs that combine both prevention and research should involve the wider international ethics community and ensure participation of the target populations in setting the proper conditions for launching such programs.

Ethical and Regulatory Issues for Embedded Pragmatic Trials Involving People Living with Dementia.

Embedded pragmatic clinical trials (ePCTs) present an opportunity to improve care for people living with dementia (PLWD) and their care partners, but they also generate a complex constellation of ethical and regulatory challenges. These challenges begin with participant identification. Interventions may be delivered in ways that make it difficult to identify who is a human subject and therefore who needs ethical and regulatory protections. The need for informed consent, a core human subjects protection, must be considered but can be in tension with the goals of pragmatic research design. Thus it is essential to consider whether a waiver or alteration of informed consent is justifiable. If informed consent is needed, the question arises of how it should be obtained because researchers must acknowledge the vulnerability of PLWD due in part to diminished capacity and also to increased dependence on others. Further, researchers should recognize that many sites where ePCTs are conducted will be unfamiliar with human subjects research regulations and ethics. In this report, the Regulation and Ethics Core of the National Institute on Aging Imbedded Pragmatic Alzheimer's disease (AD) and AD-related dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory discusses key ethical and regulatory challenges for ePCTs in PLWD. A central thesis is that researchers should strive to anticipate and address these challenges early in the design of their ePCTs as a means of both ensuring compliance and advancing science. J Am Geriatr Soc 68:S37-S42, 2020.

Cluster over individual randomization: are study design choices appropriately justified? Review of a random sample of trials.

BACKGROUND: Novel rationales for randomizing clusters rather than individuals appear to be emerging from the push for more pragmatic trials, for example, to facilitate trial recruitment, reduce the costs of research, and improve external validity. Such rationales may be driven by a mistaken perception that choosing cluster randomization lessens the need for informed consent. We reviewed a random sample of published cluster randomized trials involving only individual-level health care interventions to determine (a) the prevalence of reporting a rationale for the choice of cluster randomization; (b) the types of explicit, or if absent, apparent rationales for the use of cluster randomization; (c) the prevalence of reporting patient informed consent for study interventions; and (d) the types of justifications provided for waivers of consent. We considered cluster randomized trials for evaluating exclusively the individual-level health care interventions to focus on clinical trials where individual randomization is only theoretically possible and where there is a general expectation of informed consent. METHODS: A random sample of 40 cluster randomized trials were identified by implementing a validated electronic search filter in two electronic databases (Ovid MEDLINE and Embase), with two reviewers independently extracting information from each trial. Inclusion criteria were the following: primary report of a cluster randomized trial, evaluating exclusively an individual-level health care intervention, published between 2007 and 2016, and conducted in Canada, the United States, European Union, Australia, or low- and middle-income country settings. RESULTS: Twenty-five trials (62.5%, 95% confidence interval = 47.5%-77.5%) reported an explicit rationale for the use of cluster randomization. The most commonly reported rationales were those with logistical or administrative convenience (15 trials, 60%) and those that need to avoid contamination (13 trials, 52%); five trials (20%) were cited rationales related to the push for more pragmatic trials. Twenty-one trials (52.5%, 95% confidence interval = 37%-68%) reported written informed consent for the intervention, two (5%) reported verbal consent, and eight (20%) reported waivers of consent, while in nine trials (22.5%) consent was unclear or not mentioned. Reported justifications for waivers of consent included that study interventions were already used in clinical practice, patients were not randomized individually, and the need to facilitate the pragmatic nature of the trial. Only one trial reported an explicit and appropriate justification for waiver of consent based on minimum criteria in international research ethics guidelines, namely, infeasibility and minimal risk. CONCLUSION: Rationales for adopting cluster over individual randomization and for adopting consent waivers are emerging, related to the need to facilitate pragmatic trials. Greater attention to clear reporting of study design rationales, informed consent procedures, as well as justification for waivers is needed to ensure that such trials meet appropriate ethical standards.

Clinical Trial Portfolios: A Critical Oversight in Human Research Ethics, Drug Regulation, and Policy.

Regulators rely on clinical trials for drug approval and labeling decisions. Health systems and clinicians rely on the evidence from trials to determine treatment, and patients rely on it to decide which courses of care to undertake. Many of these stakeholders presume that the careful review of individual studies is enough to address the ethical and scientific questions that arise in clinical trials. In what follows, however, we demonstrate that explicit consideration of trial portfolios-series of trials that are interrelated by a common set of objectives-is crucial. the ethical acceptability and evidentiary probity of individual trials can change depending on the characteristics of the portfolios in which they are embedded. Second, how trial portfolios are composed, how well they are coordinated, and how efficiently they use information determines the balance of risks and benefits they present as well as their different prospects for generating socially valuable information; these three factors also raise distinct questions of justice.