A randomized comparison of two-stage versus traditional one-stage consent for a low-stakes randomized trial.

BACKGROUND/AIMS: It has been proposed that informed consent for randomized trials should be split into two stages, with the purported advantage of decreased information overload and patient anxiety. We compared patient understanding, anxiety and decisional quality between two-stage and traditional one-stage consent. METHODS: We approached patients at an academic cancer center for a low-stakes trial of a mind-body intervention for procedural distress during prostate biopsy. Patients were randomized to hear about the trial by either one- or two-stage consent (n = 66 vs n = 59). Patient-reported outcomes included Quality of Informed Consent (0-100); general and consent-specific anxiety and decisional conflict, burden, and regret. RESULTS: Quality of Informed Consent scores were non-significantly superior for two-stage consent, by 0.9 points (95% confidence interval = -2.3, 4.2, p = 0.6) for objective and 1.1 points (95% CI = -4.8, 7.0, p = 0.7) for subjective understanding. Differences between groups for anxiety and decisional outcomes were similarly small. In a post hoc analysis, consent-related anxiety was lower among two-stage control patients, likely because scores were measured close to the time of biopsy in the two-stage patients receiving the experimental intervention. CONCLUSION: Two-stage consent maintains patient understanding of randomized trials, with some evidence of lowered patient anxiety. Further research is warranted on two-stage consent in higher-stakes settings.

Rapid-Response Treatments for Depression and Requests for Physician-Assisted Death: An Ethical Analysis.

Depression is common at the end of life, and there is longstanding concern that it may affect terminally ill patients' decisions to request physician-assisted death (PAD). However, it is difficult for clinicians to determine the role of depression in a patient's PAD request. A recent case series described rapid responses to intranasal ketamine in three patients with terminal illness and comorbid depression who had requested PAD. One patient withdrew her request (which, in retrospect, had been driven by her depression) while the others maintained their requests; in all three, the rapid relief clarified the role of depression in the patients' decision-making. In addition to ketamine, there are other emerging rapid-response treatments for depression, including psilocybin with psychological support and functional connectivity-guided transcranial magnetic stimulation. We examine three key ethical implications of such treatments: their role in clarifying the decision-making capacity of depressed patients requesting PAD; the potential tension between the legal definition of irremediability in some jurisdictions and the ethical obligations of clinicians; and the likely obstacles to treatment access and their implications for equal respect for autonomy of patients.

Practical steps to identifying the research risk of pragmatic trials.

BACKGROUND: Pragmatic randomized clinical trials that compare two or more purportedly "within the standard of care" interventions attempt to provide real-world evidence for policy and practice decisions. There is considerable debate regarding their research risk status, which in turn could lead to debates about appropriate consent requirements. Yet no practical guidance for identifying the research risks of pragmatic randomized clinical trials is available. METHODS: We developed a practical, four-step process for identifying and evaluating the research risk of pragmatic trials that can be applied to those pragmatic randomized clinical trials that compare two or more "standard of care" or "accepted" interventions. RESULTS: Using a variety of examples of standard of care pragmatic randomized clinical trials (ranging from trials comparing: insurance coverage conditions, patient reminders for health screens, intensive care unit procedures, post-stroke interventions, and drugs for life-threatening conditions), we illustrate in a four-step process how any pragmatic randomized clinical trial purportedly comparing standard interventions can be evaluated for their research risks. CONCLUSION: Although determining the risk status of a standard of care pragmatic randomized clinical trial is only one necessary element in the ethical oversight of such pragmatic randomized clinical trials, it is a central element. Our four-step process of pragmatic randomized clinical trial risk determination provides a practical, transparent, and systematic approach with likely low risk of bias.

Assessing Public's Attitudes Towards Euthanasia and Assisted Suicide of Persons With Dementia Based on Their Advance Request: An Experimental Survey of US Public.

OBJECTIVE: Advance request euthanasia and/or assisted suicide (AR-EAS) in persons with dementia is highly controversial. Results of typical public opinion surveys may not reflect the ethical and practical issues involved in the practice. We tested the impact of incorporating such issues in the assessment of public attitudes toward legalization of AR-EAS. DESIGN: Online survey (April 27-30, 2020) of 1,711 adults recruited via CloudResearch PrimePanel, matched to U.S. population in age, sex, race and/or ethnicity, education, household income, and political affiliation. After assessing initial attitudes toward legalization of AR-EAS, respondents viewed one of six randomly assigned scenarios depicting an ethical or practical issue in AR-EAS; acceptability of EAS in each scenario as well as general attitudes toward AR-EAS legalization were then elicited. RESULTS: Approximately 54.4% initially agreed/strongly agreed with AR-EAS legalization; agreement was associated with lower dementia quality-of-life rating, younger age, not being religious, liberal politics, and $75,000-$99,999 income range. After viewing the scenarios, a minority in each scenario arm found the AR-EAS depicted acceptable (20.7%-39.1%; p<0.0001 for all six arms, in comparison with initial legalization question response). Support (agree/strongly agree) for AR-EAS legalization after reading specific scenarios was generally lower (range 36.5%-49.3%; p≤0.0002); change in support for legalization was associated with initial support for legalization, acceptability of AR-EAS in the scenarios, dementia quality-of-life ratings, and race. CONCLUSION: Informing the public of the ethical and practical complexities in AR-EAS may have significant effects on their attitudes toward legalization. Future surveys should ensure that the public's views reflect sufficient exposure to these complexities.

Is this person with dementia (currently) competent to request euthanasia? A complicated and underexplored question.

In euthanasia and/or assisted suicide (EAS) of persons with dementia, the controversy has mostly focused on decisionally incapable persons with very advanced dementia for whom the procedure must be based on a written advance euthanasia directive. This focus on advance euthanasia directive-based EAS has been accompanied by scant attention to the issue of decision-making capacity assessment of persons with dementia who are being evaluated for concurrent request EAS. We build on a previous analysis of concurrent request EAS cases from the Netherlands, which showed that many such cases involve persons with significant cognitive impairment. We use illustrative cases to describe the difficulty of determining decisional capacity in persons whose stage of dementia falls between severely impaired and mildly impaired. We show that the Dutch practice of capacity assessment in such dementia cases is difficult to reconcile with the widely accepted functional model of capacity-a model explicitly endorsed by the Dutch euthanasia review committees. We discuss why such deviations from the standard functional model might be occurring, as well as their ethical implications for dementia EAS policy and practice.

Understanding preferences regarding consent for pragmatic trials in acute care.

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.

Just-in-time consent: The ethical case for an alternative to traditional informed consent in randomized trials comparing an experimental intervention with usual care.

Informed consent for randomized trials often causes significant and persistent anxiety, distress and confusion to patients. Where an experimental treatment is compared to a standard care control, much of this burden is potentially avoidable in the control group. We propose a "just-in-time" consent in which consent discussions take place in two stages: an initial consent to research from all participants and a later specific consent to randomized treatment only from those assigned to the experimental intervention. All patients are first approached and informed about research procedures, such as questionnaires or tests. They are also informed that they might be randomly selected to receive an experimental treatment and that, if selected, they can learn more about the treatment and decide whether or not to accept it at that time. After randomization, control patients undergo standard clinical consent whereas patients randomized to the experimental procedure undergo a second consent discussion. Analysis would be by intent-to-treat, which protects the trial from selection bias, although not from poor acceptance of experimental treatment. The advantages of just-in-time consent stem from the fact that only patients randomized to the experimental treatment are subject to a discussion of that intervention. We hypothesize that this will reduce much of the patient's burden associated with the consent process, such as decisional anxiety, confusion and information overload. We recommend well-controlled studies to compare just-in-time and traditional consent, with endpoints to include characteristics of participants, distress and anxiety and participants' understanding of research procedures.

Ethics and practice of Trials within Cohorts: An emerging pragmatic trial design.

BACKGROUND: With increasing emphasis on pragmatic trials, new randomized clinical trial designs are being proposed to enhance the "real world" nature of the data generated. We describe one such design, appropriate for unmasked pragmatic clinical trials in which the control arm receives usual care, called "Trials within Cohorts" that is increasingly used in various countries because of its efficiency in recruitment, advantages in reducing subject burden, and ability to better mimic real-world consent processes. METHODS: Descriptive, ethical, and US regulatory analysis of the Trials within Cohorts design. RESULTS: Trials within Cohorts design involves, after recruitment into a cohort, randomization of eligible subjects, followed by an asymmetric treatment of the two arms: those selected for the experimental arm provide informed consent for the intervention trial, while the data from the control arm are used based on prior broad permission. Thus, unlike the traditional Zelen post-randomization consent design, the cohort participants are informed about future research within the cohort; however, the extent of this disclosure currently varies among studies. Thus, ethical analysis is provided for two types of situations: when the pre-randomization disclosure and consent regarding the embedded trials are fairly explicit and detailed versus when they consist of only general statements about future data use. These differing ethical situations could have implications for how ethics review committees apply US research rules regarding waivers and alterations of informed consent. CONCLUSION: Trials within Cohorts is a promising new pragmatic randomized controlled trial design that is being increasingly used in various countries. Although the asymmetric consent procedures for the experimental versus control arm subjects can initially raise ethical concerns, it is ethically superior to previous post-randomization consent designs and can have important advantages over traditional trial designs.

A framework for analysis of research risks and benefits to participants in standard of care pragmatic clinical trials.

BACKGROUND/AIMS: Standard of care pragmatic clinical trials that compare treatments already in use could improve care and reduce costs, but there is considerable debate about the research risks of standard of care pragmatic clinical trials and how to apply informed consent regulations to such trials. We sought to develop a framework integrating the insights from opposing sides of the debate. METHODS: We developed a formal risk-benefit analysis framework for standard of care pragmatic clinical trials and then applied it to key provisions of the US federal regulations. RESULTS: Our formal framework for standard of care pragmatic clinical trial risk-benefit analysis takes into account three key considerations: the ex ante estimates of risks and benefits of the treatments to be compared in a standard of care pragmatic clinical trial, the allocation ratios of treatments inside and outside such a trial, and the significance of some participants receiving a different treatment inside a trial than outside the trial. The framework provides practical guidance on how the research ethics regulations on informed consent should be applied to standard of care pragmatic clinical trials. CONCLUSION: Our proposed formal model makes explicit the relationship between the concepts used by opposing sides of the debate about the research risks of standard of care pragmatic clinical trials and can be used to clarify the implications for informed consent.

Are patients with amyotrophic lateral sclerosis at risk of a therapeutic misconception?

OBJECTIVES: To assess whether persons with amyotrophic lateral sclerosis (ALS) are at risk of a therapeutic misconception (TM) in which they misconceive research as treatment or overestimate the likelihood of its benefit. METHODS: 72 patients with ALS recruited via academic and patient organisations were surveyed using a hypothetical first-in-human intervention study scenario. We elicited their understanding of the purpose of the study ('purpose-of-research question') and then asked how they interpreted the question. We then asked for an estimate of the likelihood that their ALS would improve by participating and asked them to explain the meaning of their estimates. RESULTS: Although 10 of 72 (14%) subjects incorrectly said that the intervention study was 'mostly intending to help [me]' in response to the purpose-of-research question, 7 of those 10 thought that the question was asking them about their own motivations for participating. Overall, only one of 72 respondents (1.4%) both understood the purpose-of-research question as intended and gave the incorrect response. Subjects' mean estimate of likelihood of benefit was 31% (SD 26). This was due to 29 of 72 of respondents providing high estimates (50%-54% likelihood), which they said were expressions of hope and need for a positive attitude; among those who said their estimates meant 'those are the facts' or 'there is a lot of uncertainty', the estimates were much lower (12.6% and 18.5%, respectively). CONCLUSIONS: In this group of patients with ALS considering a hypothetical first-in-human intervention study, apparent TM responses have alternative explanations and the risk of true TM appears low.