Risk to Research Non-Participants: Ethical Dimensions of Protecting Bystanders in Xenotransplantation Clinical Trials
Conference Presentation – IPITA-IXA-CTRMA 2023 Joint Congress Abstracts
Daniel Hurst, Luz Padilla, Daniel Rodger, Tamar Schiff, David KC Cooper
Transplantation, October 2023
Abstract
Introduction
Ethical issues regarding clinical xenotransplantation have been described for decades with most of the issues centering on animal welfare, the risks posed to the recipient, and the potential public health risks. Much less attention has been given to thinking through ethical issues for those who may care for xenograft recipients (e.g., caregivers, family members), especially when the recipient returns home. These caregivers or bystanders, due to their close interaction with the xenotransplantation recipient, face potential exposure to a xenozoonotic disease, with implications regarding informed consent for that risk, and whether or not such bystanders should be regularly monitored for infection, as is proposed for recipients.
Methods
This presentation raises concerns for the risks to bystanders in xenotransplantation which we believe have not been adequately addressed in the literature to date. We will propose several options for how bystanders should be informed of, and consented for, the risks of close contact with a xenotransplant recipient. The benefits and pitfalls of each potential option are explored.
Results
We conclude that only the xenograft recipient needs to provide their informed consent to the xenotransplantation and agree to lifelong (or long-term) monitoring. As no legal enforcement mechanism currently exists for requiring recipients to be monitored without evidence of infectious disease, such monitoring could only be strongly encouraged and agreed to at the point of xenotransplantation, but not required. In addition, we argue that the xenograft recipient, prior to xenotransplantation, should provide a list of members of the same household/close contacts for record keeping and future possible contact tracing. We propose at a minimum that all members listed should be provided with an information sheet or assent form that contains the basic elements of the informed consent form but does not require a signature or other declaration of agreement. This approach seeks to balance ethical concerns, namely the potential risks posed to bystanders and how strong a duty this creates to protect them and support their right to choose how or if they contiue to interact with the potential xenograft recipient, with the recipient’s reasonable right to patient privacy.
Conclusion
This presentation discusses a significant concern related to xenotransplantation, made increasingly pressing by the possibility of forthcoming clinical trials. By the end of the presentation, the audience will better understand the bystander risk, differing modes of mitigating that risk, and why it is important to foster dialogue and develop policy on this issue.

Optimizing Informed Consent in Cancer Clinical Trials
Subha Perni, Rachel Jimenez, Reshma Jagsi
Seminars in Radiation Oncology, October 2023; 33(4) pp 349-357
Abstract
The concept of informed consent has evolved considerably over the course of the 20th century, leading to its establishment as a foundational ethical principle for the conduct of biomedical research in the United States. Even though it is now a highly regulated part of cancer research, the process of obtaining informed consent is often impeded by systemic, clinician, and patient factors that require both small- and large-scale intervention. New challenges and considerations continue to emerge due to innovations in clinical trial design, increases in utilization of genomic sequencing, and advances in genomic editing and artificial intelligence. We present a review of the history, policy, pragmatic challenges, and evolving role of the central ethical tenet of informed consent in clinical trials.

Simplified consent in cluster randomised trials: the new EU Clinical Trials Regulation does not provide sufficient guidance
Analysis
Cory E Goldstein
BMJ, 13 September 2023
Excerpt
    The new European Union (EU) Clinical Trials Regulation 536/2014 is designed to streamline and harmonise the submission and review process for clinical trials conducted in EU member states and countries in the European Economic Area. Since 31 January 2023, clinical trial applications in the EU must be submitted through the Clinical Trials Information System and must abide by the regulation.

This includes applications to conduct cluster randomised trials (CRTs), which are commonly used for the evaluation of public health, health policy, and health system interventions. In contrast to individually randomised trials in which people are randomly allocated to receive study interventions, in CRTs intact groups (such as geographical areas or clinics) are randomly assigned to receive the study interventions. Study interventions can be delivered to the entire cluster as a unit (such as a mass media smoking cessation campaign on the radio) or to professionals in each cluster (such as educational workshops for health providers to improve hand hygiene), but only CRTs that evaluate medicinal products delivered to patients in each cluster fall under the purview of the EU Clinical…

How do journals publishing palliative and end-of-life care research report ethical approval and informed consent?
Original Article
Tove Godskesen, Knut Jørgen Vie, William Bülow, Bodil Holmberg, Gert Helgesson, Stefan Eriksson
Learned Publishing, 8 September 2023
Open Access
Abstract
This study explores how papers published in international journals in palliative and end-of-life care report ethical approval and informed consent. A literature search following PRISMA guidelines was conducted in PubMed, the Web of Science Core Collection, Scopus, the ProQuest Social Science Premium Collection, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). A total of 169 empirical studies from 101 journals were deductively coded and analysed. The results showed that 5% of publications provided no information on ethical approval, 12% reported minimal information, 56% reported rudimentary information, and 27% reported comprehensive details. We also found that 13% did not report any information on informed consent, 17% reported minimal information, 50% reported rudimentary information, and 19% reported comprehensive details. The prevalence of missing and incomplete ethical statements and inadequate reporting of informed consent processes in recent publications raises concerns and highlights the need for improvement. We suggest that journals advocate high reporting standards and potentially reject papers that do not meet ethical requirements, as this is the quickest path to improvement.

Analysis of ethical review issues of informed consent form for clinical trials of registered anti-tumor drugs in our hospital
Xiaohua Tang, Yi Bi, Xia Chen, Jun Li, Haiwei Zhang
China Pharmacy, 2023; 12 pp 648-652
Abstract
Objective
To promote the standardization and integrity of the informed consent form for clinical trials of registered anti-tumor drugs, and to protect the legitimate rights and interests of the subjects.
Methods
The ethical review resolutions of clinical trial projects of registered anti-tumor drugs that were initially reviewed by the Ethics Committee of our hospital from July 1st, 2020 to July 1st, 2022 were summarized to statistically analyze the problematic items according to the “Quality Analysis Form of Informed Consent” prepared by our hospital.
Results
Of the 316 clinical trials of registered anti-tumor drugs that were initially reviewed, 257 (81.3%) had problems with the contents of informed consent form, mainly domestic multi-center trials and phase three trials. The main problems included the vague notification of the test fee bearer (68.5%), the incomplete notification of the test content (59.1%), the insufficient notification of rights and interests and risks (58.4%), the insufficient notification of personal information protection (56.0%), and the nonstandard expression of the informed consent form (52.5%).
Conclusions
There is still a gap between the informed consent form of the clinical trials of registered anti-tumor drugs in our hospital and the requirements of the new version of Good Clinical Practice for Drugs (GCP). The parties involved in the test can take a number of measures to improve the standardization and integrity of the informed consent form, and the research team should design the informed consent form in strict accordance with the requirements of the new GCP and pay attention to the comprehensive notification about the test. The Ethics Committee can provide the sponsor and researcher with the template of informed consent form and the key points of writing, continue to strengthen the examination ability, improve the examination quality, and effectively protect the safety and interests of the subjects.

Consent document translation expense hinders inclusive clinical trial enrolment
Maria A. Velez, Beth A. Glenn, Maria Garcia-Jimenez, Amy L. Cummings, Aaron Lisberg, Andrea Nañez, Yazeed Radwan, Jackson P. Lind-Lebuffe, Paige M. Brodrick, Debory Y. Li, Maria J. Fernandez-Turizo, Arjan Gower, Maggie Lindenbaum, Manavi Hegde, Jenny Brook, Tristan Grogan, David Elashoff, Michael A. Teitell, Edward B. Garon
Nature, 2 August 2023
Abstract
Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA. As these patients often have limited English proficiency, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor). Here we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry-sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient’s primary language in studies without industry sponsorship was approximately half of that seen in industry-sponsored studies. The results suggest that the cost of consent document translation in trials not sponsored by industry could be a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

Advance Consent In Acute Stroke Trials: Survey Of Canadian Research Ethics Board Chairs
Manuscript
Rena Seeger, Ubong Udoh, Brian Dewar, Stuart Nicholls, Mark Fedyk, Robert Fahed, Jeff Perry, Michael D Hill, Bijoy Menon, Richard H Swartz, Alexandre Y Poppe, Sophia Gocan, Jamie Brehaut, Katie Dainty, Victoria Shepherd, Dar Dowlatshahi, Michel Shamy
24 July 2023 [Cambridge University Press]
Abstract
Advance consent could allow individuals at high risk of stroke to provide consent before they might become eligible for enrollment in acute stroke trials. This survey explores the acceptability of this novel technique to Canadian Research Ethics Board (REB) chairs that review acute stroke trials. Responses from 15 REB chairs showed that majority of respondents expressed comfort approving studies that adopt advance consent. There was no clear preference for advance consent over deferral of consent, although respondents expressed significant concern with broad rather than trial-specific advance consent. These findings shed light on the acceptability of advance consent to Canadian ethics regulators.

A randomized comparison of two-stage versus traditional one-stage consent for a low-stakes randomized trial
Research Article
Andrew J Vickers, Emily A Vertosick, Mia Austria, Christopher D Gaffney, Sigrid V Carlsson, Scott YH Kim, Behfar Ehdaie
Clinical Trials, 4 July 2023
Abstract
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.

Informed consent practices in clinical research: present and future
Natasha A Jawa, J Gordon Boyd, David M Maslove, Stephen H Scott, Samuel A Silver
Postgraduate Medical Journal, 2 June 2023
Abstract
Clinical research must balance the need for ambitious recruitment with protecting participants’ autonomy; a requirement of which is informed consent. Despite efforts to improve the informed consent process, participants are seldom provided sufficient information regarding research, hindering their ability to make informed decisions. These issues are particularly pervasive among patients experiencing acute illness or neurological impairment, both of which may impede their capacity to provide consent. There is a critical need to understand the components, requirements, and methods of obtaining true informed consent to achieve the vast numbers required for meaningful research. This paper provides a comprehensive review of the tenets underlying informed consent in research, including the assessment of capacity to consent, considerations for patients unable to consent, when to seek consent from substitute decision-makers, and consent under special circumstances. Various methods for obtaining informed consent are addressed, along with strategies for balancing recruitment and consent.

Trusting relationships between patients with non-curative cancer and healthcare professionals create ethical obstacles for informed consent in clinical trials: a grounded theory study
Mary Murphy, Eilis McCaughan, Gareth Thompson, Matthew A. Carson, Jeffrey R Hanna, Monica Donovan, Richard Wilson, Donna Fitzsimons
BMC Palliative Care, 21 June 2023
Abstract
Background
Clinical trial participation for patients with non-curative cancer is unlikely to present personal clinical benefit, which raises the bar for informed consent. Previous work demonstrates that decisions by patients in this setting are made within a ‘trusting relationship’ with healthcare professionals. The current study aimed to further illuminate the nuances of this relationship from both the patients’ and healthcare professionals’ perspectives.
Methods
Face-to-face interviews using a grounded theory approach were conducted at a regional Cancer Centre in the United Kingdom. Interviews were performed with 34 participants (patients with non-curative cancer, number (n) = 16; healthcare professionals involved in the consent process, n = 18). Data analysis was performed after each interview using open, selective, and theoretical coding.
Results
The ‘Trusting relationship’ with healthcare professionals underpinned patient motivation to participate, with many patients ‘feeling lucky’ and articulating an unrealistic hope that a clinical trial could provide a cure. Patients adopted the attitude of ‘What the doctor thinks is best’ and placed significant trust in healthcare professionals, focusing on mainly positive aspects of the information provided. Healthcare professionals recognised that trial information was not received neutrally by patients, with some expressing concerns that patients would consent to ‘please’ them. This raises the question: Within the trusting relationship between patients and healthcare professionals, ‘Is it possible to provide balanced information?’. The theoretical model identified in this study is central to understanding how the trusting professional-patient relationship influences the decision-making process.
Conclusion
The significant trust placed on healthcare professionals by patients presented an obstacle to delivering balanced trial information, with patients sometimes participating to please the ‘experts’. In this high-stakes scenario, it may be pertinent to consider strategies, such as separation of the clinician-researcher roles and enabling patients to articulate their care priorities and preferences within the informed consent process. Further research is needed to expand on these ethical conundrums and ensure patient choice and autonomy in trial participation are prioritised, particularly when the patient’s life is limited.