Advanced Consent Research Articles

PEMBROCABOSARC: Combination of pembrolizumab and cabozantinib in patients with advanced sarcomas.

TPS11586 Background: Despite optimal treatment, up to 40% of patients with sarcomas will develop locoregional and/or distant relapse and median survival in this setting is less than two years. There are very few options in the treatment of undifferentiated pleomorphic sarcomas whereas there is no specific treatment regimen established for recurrent osteosarcoma (OSS) and Ewing sarcoma (ES). Innovative strategies are therefore urgently needed in these settings. In preclinical studies, while immune checkpoint inhibitors were insufficient in controlling tumour growth, combining them with M2 macrophage or angiogenesis targeting resulted in superior tumour control (Mao et al, Clin Cancer Res 2016; Zhu et al, Cancer Res 2014). Combining both antiangiogenic and MET inhibition properties, cabozantinib has shown both preclinical and clinical activity, notably in osteosarcoma and Ewing sarcoma (Italiano et al. ESMO 2018). Interestingly, cabozantinib has also recently been shown to trigger an innate immune response in a preclinical model (Patnaik et al, Cancer Discov 2017). Altogether, these findings pave the way for studies assessing the impact of targeting angiogenesis, MET and immune response in soft-tissue and bone sarcomas. Methods: PEMBROCABOSARC (NCT05182164) is a multi-stratum, three single-arm phase 2, multicenter, open-label study investigating pembrolizumab combined with cabozantinib in patients with advanced selected sarcomas: undifferentiated pleomorphic sarcoma (stratum 1), osteosarcoma (stratum 2), Ewing sarcoma (stratum 3). Strata 1 and 2 will enroll ~32 patients and stratum 3 ~55 patients, respectively. Each stratum phase II will be conducted using a Simon's optimal two-stage design. Eligible and consented patients must be ECOG PS 0–1, have measurable and progressive disease according to RECIST 1.1 and have received less than 3 previous lines of systemic therapy for advanced disease and consent also to baseline and per treatment biopsies. Cabozantinib will be administered orally, once daily at a fixed dose of 40 mg, continuously. Pembrolizumab will be administered by intravenous infusion every 3 weeks on Day 1 of each cycle, at a fixed dose of 200 mg. Both treatments will start on Day 1 (of cycle 1). The primary endpoint is 6-months non progression rate as per RECIST 1.1. Secondary endpoints include adverse events (AEs)/serious AEs, best overall response, and progression-free survival. Pharmacodynamic and other biomarkers will be explored on blood and tumor tissue. The first patient received study drug on May, 31, 2022; 8 of planned 119 patients have been enrolled and 5 sites across France among the planned 10, are currently enrolling patients. Clinical trial information: NCT05182164 .

Factors influencing the involvement of health care professionals in the administration of medical aid in dying in Quebec

On February 16, 2023, the Quebec provincial Minister for Health and Seniors introduced Bill 11, which would allow people suffering from serious and incurable diseases to benefit from medical aid in dying (MAID) through an advanced consent, in anticipation of incapacity. In addition, people with severe neuromotor disabilities such as quadriplegia would also be eligible for MAID if they meet the other eligibility criteria. If this bill is adopted, we can expect the number of MAID to increase in the coming years. Moreover, the number of HCPs who agree to be involved in the process of administering MAID remains relatively stable and objectively low, which generates an additional clinical, psychological and administrative burden for HCPs who agree to provide this care. Through a narrative review of the scientific literature, we found that there have been very few empirical studies about the factors that contribute (positively or negatively) to HCP involvement in the MAID process. The data show that among the factors that have been identified in the scientific literature as discouraging the involvement of HCPs in MAID, some are related to HCPs’ freedom of conscience and their core values, while others are more pragmatic and emerge from the reality of the field. Many factors influence negatively HCP participation in MAID. However, some of these factors, specifically those that are not related to the exercise of freedom of conscience, may potentially be mitigated by the implementation of appropriate resources, such as the creation of a space for safe dialogue. This article highlights the heterogeneity of factors that can interfere with the involvement of HCPs in MAID and, above all, the need for further investigation of these issues in order to adequately take them into consideration in the organization and provision of care.

Advance Directives and Research Advance Directives

Advance Directives and Research Advance Directives

Abstract P284: Coordinating Options for Acute Stroke Therapy (COAST): Demonstrating Patient Autonomy by Examining Preferences for Acute Stroke Treatment From a Stroke Advance Directive

Introduction: Respect for patient autonomy is critical, and patients/surrogates may have various preferences about acute stroke treatment that are not fully appreciated during a stroke code. COAST (Coordinating Options for Acute Stroke Therapy) is a stroke advance directive formalizing advanced consent for thrombolysis (tPA) and endovascular therapy (EVT). We examine the distribution of patient preferences to improve understanding and respect for patient autonomy in acute stroke. Methods: In our IRB-approved study, we collected COAST forms at UC San Diego from 12/1/2014-2/29/2020. Patients chose one of five tPA preferences: not under any circumstance (tPA 1); up to 3 hours only, based on FDA approval (tPA 2); up to 4.5 hours only, based on current guidelines (tPA 3); anytime per provider discretion (tPA 4); or other answer (tPA treatment under specific conditions written by the patient/surrogate) (tPA 5). Patients also chose one of five EVT preferences: not under any circumstance (EVT 1); up to 6 hours only (EVT 2); up to 12 hours only (EVT 3); up to 24 hours only (this option replaced "up to 12 hours only" on 3/1/2018 when the 6-24 hour window became standard of care) (EVT 4); anytime at provider discretion (EVT 5); or other answer (EVT treatment under specific conditions written by the patient/surrogate) (EVT 6). Frequency of preferences was calculated for each option. Results: In total, 342 COASTs were completed. Frequency of tPA preferences were: 3.2% for tPA 1 (11/342), 1.5% for tPA 2 (5/342), 25.7% for tPA 3 (88/342), 55.6% for tPA 4 (190/342), 14.0% for tPA 5 (48/342). Frequency of EVT preferences were: 1.8% for EVT 1 (6/342), 9.6% for EVT 2 (33/342), 3.2% for EVT 3 (11/342), 10.8% for EVT 4 (37/342), 62.3% for EVT 5 (213/342), 12.3% for EVT 6 (42/342). When the 6-24 hour window became standard of care, 0% (0/342) chose EVT 2. Total 81.6% (n=279) of COASTs had the same tPA and EVT preferences, and 18.4% (n=63) had tPA preferences that were different from EVT preferences. Conclusion: Preferences vary regarding tPA and EVT treatment. Most patients defer to provider discretion, though some patients have preferences that are different from current provider expectations and/or stroke guidelines. COAST is pivotal to inform respect for patient autonomy for acute stroke codes.

Case Report: The use of advanced consent methodology and healthcare professional consultee to facilitate research participation in dying patients

As the need for palliative care increases, it is essential for research opportunities to be offered to patients with palliative care needs to ensure patients can receive evidence-based treatments and services to improve care. Although it is recognised that palliative, and in particular end of life, research can be both methodically and ethically challenging it is important to note that palliative patients are keen to be involved with research. Over the past three years, patients in Marie Curie Hospice Liverpool have been recruited to a research study evaluating hydration, where advance consent methodology is used to facilitate participation at the end of life. In this study, participants provided ‘advanced consent’ to receive research assessments, in anticipation of the deterioration of their health and loss of the ability to provide consent to ongoing research participation. During this process, recruiting participants will nominate a consultee (who can be any family member, friend or healthcare professional), who is contacted by the researcher prior to completion of research assessments. Participants will generally choose a caregiver or friend to act as a personal consultee; however, there may be some instances where a healthcare professional is chosen. In this, we share our experiences using advanced consent methodology and a healthcare professional acting as a consultee, to facilitate research assessments in a patient who was lacking capacity at the end of life.

Advanced consent for participation in acute care randomised control trials: protocol for a scoping review

IntroductionInformed consent is essential to clinical research, though obtaining informed consent for participation in research for emergency conditions is challenging. Adapted consent methods include consent from a substitute-decision maker, deferral...

Medical Assistance in Dying: Patients', Families', and Health Care Providers' Perspectives on Access and Care Delivery.

Background: Medical assistance in dying (MAID) became legal in Canada in 2016. Although the legislation is federal, each province is responsible for establishing quality care. Objective: To explore patient, family, and health care provider (HCP) perspectives on MAID access and care delivery and improve regional MAID care delivery. Design: Qualitative exploratory. Setting/Subjects: We interviewed 5 patients (4 met the legislated MAID criteria and 1 did not), 11 family members (4 spouses, 5 children, 1 sibling, and 1 friend), and 14 HCP (3 physicians, 4 social workers, and 7 nurses) from June to August 2017. Measurement: Semistructured interviews, content analysis, and thematic summary. Results: Patients, families, and HCPs highlighted access and delivery concerns regarding program sustainability, care pathway ambiguity, lack of support for care choices, institutional conscientious objection (CO), navigating care in institutions with a CO, and postdeath documentation. Patients and families expressed additional concerns regarding lack of ability to provide advanced MAID consent, and the requirement of independent witnesses on MAID request forms and consent immediately before MAID administration. HCPs were additionally uncertain about professional roles and responsibilities. Ten recommendations to improve regional MAID care and the resultant practice change are presented. Conclusion: Quality improvement (QI) processes are essential to devise an accessible dignified patient- and family-centered MAID program. Ensuring patient and family perspectives are integrated into QI initiatives will assist programs in ensuring the needs of all are considered in structuring and staffing a program that is accessible, easy to navigate, and provides dignified end-of-life care in supportive and respectful work environments.

Public attitudes towards research participation during an infectious disease pandemic: a qualitative study across four European countries

BackgroundPandemics of infectious disease are recurrent events that impact global health and security. International, collaborative planning for future pandemics is a priority for public health officials, the research community, and the general public. However, little is known about the public's attitudes to participating in pandemic research and about their views on associated ethical dilemmas. We aimed to determine public perceptions about involvement in clinical research conducted in primary and critical care during a pandemic. MethodsWe conducted ten, 2 hour focus groups (6–10 participants each) and 16 one-to-one follow-up interviews involving 80 members of the public in Belgium, Poland, Spain, and the UK between Sept 1 and Dec 31, 2015. Recruitment was through local advertisement. Data were collected by local researchers who followed a scenario-based topic guide, transcribed verbatim and translated into English. We used framework analysis to identify the range and diversity of participants' perspectives. FindingsPublic understandings of pandemics were shaped by personal factors (illness during the H1N1 pandemic, experience of life-threatening illness) and social factors (historical references, media, public health information). Motivations to participate in pandemic research were influenced by altruism, therapeutic misconception, trust, and perception of risk. Use of routinely collected data and clinical samples without explicit prior consent was supported in principle, but was less acceptable when a profit motive was perceived. Participants recognised and appreciated the protections provided by ethically robust research procedures. However, they described having become desensitised to the importance and meaning of consent processes because of the frequency with which they authorise terms and conditions in everyday life. Participants proposed different models that might apply in a pandemic context (eg, advanced consent, verbal consent). InterpretationPublic engagement in clinical research on pandemic planning is possible, useful, but as yet underdeveloped in Europe. Effective pandemic preparation for clinical research requires active public engagement to mitigate therapeutic misconception and engender trust. This bottom-up approach to ascertaining public views on pandemic research participation has identified support for minimising disproportionate research protection procedures for publicly funded, low risk studies. FundingEuropean Union Seventh Framework Programme under the project Platform foR European Preparedness Against (Re-)emerging Epidemics (PREPARE) (grant agreement 602525).

Ethics of Clinical Research Involving Adults with Impaired Decision-Making Capacity

Background: Proper decision making capacity, adequate disclosure and voluntary decisions are basic constituents of informed consent which is required in surgical procedures, any interventions, any tissue collection, or any research involving the human participants. But, it becomes more hectic if the participants or patients are physically or mentally impaired for proper understanding or rational decision making. Time has gone by assembling or regulating effective laws for research involving persons with impaired decision making capacity. Still, question arises, is it ethical to enroll an incompetent person who is not physically or mentally fit to make a decision in risky research or interventional trials? If it is, how the informed consent and ethical measures can be taken? Method: Extensive literature review was done in Google scholar, PubMed and national or institutional websites with the corresponding keywords to summarize the cases of impaired decision making and regulation of informed consent and ethical measures in those cases. Results: Decision making capacity requires three level of capacities and four levels of abilities. If a person has factual understanding, implies a certain level of rational belief, knows to manipulate information to arrive at a choice and remains stable on the choice, is known to be capacitated in decision making. Impaired decision making capacity is more common in Alzheimer’s disease and schizophrenia research. Although a definite line between decisional capacity and incapacity is still in question, many assessment tools are available to conclude it. Moreover, decisional incapacity has been found as a significant ratio in general or psychiatric hospitals and nursing homes regarding psychological disorders or critically ill conditions. But, these conditions should not prevent anyone from understanding, choosing, or accepting any intervention as sometimes they may have some preserved abilities too. As per accepted ethics, respect for persons incorporates at least two ethical convictions. First, the individual should be treated as an autonomous agent and second, the person with diminished autonomy is entitled to protection. That’s why, in case of severe psychiatric diseases and Alzheimer’s diseases, surrogate consent is recommended. But surrogacy should be reviewed by the institutional review board (IRB). Multimedia consent process, advanced consent directives, rational consent waiver and many other processes are practiced in case of ethical research involving decisional incapacitate persons which are discussed in the paper. Conclusion: It should be clarified by the IRB whether involvement of impaired subjects has beneficial scientific aim or not. Capacity assessment system should be in an organized and systemic way. Threshold for capacity and recognition of persons able to conduct this process should be fixed. Role of surrogacy and involvement of IRB to align it in a proper manner is always a matter of concern. Consideration of risk management, subjects’ autonomy and assent-dissent issues should be clarified in research.

WHICH CLINICAL MEASURES ARE MOST APPROPRIATE FOR MEASURING DISEASE PROGRESSION IN PARKINSON'S DISEASE?

ObjectivesTo determine which clinical measures of disease progression in Parkinson's disease (PD) can feasibly be measured across the disease spectrum and which are most sensitive to change.BackgroundUnderstanding the feasibility of...

Consent, including advanced consent, of older adults to research in care homes: a qualitative study of stakeholders' views in South Wales.

BackgroundCare home residents, especially those lacking capacity to provide consent for themselves, are frequently excluded from research, thus limiting generalisability of study findings. We set out to explore stakeholders’ views about the ethical and practical challenges associated with recruiting care home residents into research studies.MethodsQualitative individual interviews with care home residents (n = 14), their relatives (n = 14), and general practitioners (GPs) (n = 10), and focus groups (n = 2) with care home staff. Interviews focused on the issues of older adults consenting to research in care homes, including advanced consent, in general and through reference to a particular study on the use of probiotics to prevent Antibiotic Associated Diarrhoea. Data were analysed using a thematic approach incorporating themes that had been identified in advance, and themes derived from the data. Researchers discussed evidence for themes, and reached consensus on the final themes.ResultsRespondents were generally accepting of low risk observational studies and slightly less accepting of low risk randomised trials of medicinal products. Although respondents identified some practical barriers to informed consent, consenting arrangements were considered workable. Residents and relatives varied in the amount of detail they wanted included in information sheets and consent discussions, but were generally satisfied that an advanced consent model was acceptable and appropriate. Opinions differed about what should happen should residents lose capacity during a research study.ConclusionsResearch staff should be mindful of research guidance and ensure that they have obtained an appropriate level of informed consent without overwhelming the participant with unnecessary detail. For research involving medicinal products, research staff should also be more explicit when recruiting that consent is still valid should an older person lose capacity during a trial provided the individual did not previously state a wish to be withdrawn if they lose capacity, and provided they do not indicate objection or resistance after loss of capacity.

Every Breath You Take: Erotic Asphyxiation, Vengeful Wives and Other Enduring Myths in Spousal Sexual Assault Prosecutions

The Supreme Court of Canada’s important decision in J.A. should end reliance on the defence of advanced consent thereby helping to ensure that women who are unconscious for any reason are protected from sexual assault. A closer analysis of the case and related jurisprudence also reveals that this decision does not support fears that BDSM practitioners now face heightened risk criminal prosecutions. But it illuminates other serious problems that arise, especially in spousal sexual assaults prosecutions, including minimization of the harms of strangulation, a willing to see violence as enjoyable, and the continued reliance of sexual history evidence without more contextualizing information, especially the defendant’s prior violence against the complainant. It also raises questions about whether and when expert evidence is required in spousal sexual assault cases.

Exploring the ethical and practical challenges of conducting clinical trials in care home settings

Background The PAAD Study (Probiotics for Antibiotic Associated Diarrhoea in care homes) involves 2 stages. The first stage is a prospective 12 month observational study to collect data on the amount and type of antibiotic prescribed episodes of Antibiotic Associated Diarrhoea and C.difficile Associated Diarrhoea and outcome in a randomly selected sample of 9 care homes. The second stage is currently being designed but will take the form of a RCT of probiotic vs. placebo administered alongside the antibiotic. These two studies are governed by separate laws and regulations in relation to mental capacity. PAAD stage 1 is covered by the Mental Capacity Act and, for those service users who lack capacity, personal consultees are able to give agreement to the service user’s participation. PAAD stage 2 is covered by the Medicines for Human Use (Clinical Trials) Regulations and consent is given by a personal legal representative or a professional legal representative of the participant. The PAAD study also presents novel challenges in relation to advanced consent. We propose to explore some of the ethical and practical challenges of conducting these studies (and others like it) within the care home setting using qualitative methods. Our purpose is to optimise the informed consent process in a vulnerable population in preparation for stage two of PAAD.

Comment on “Limits on Fluorescence Detected Circular Dichroism of Single Helicene Molecules”

Comment on “Limits on Fluorescence Detected Circular Dichroism of Single Helicene Molecules”