Advancing Randomized Clinical Trials in Surgery: Role of Exception From Informed Consent, Central Institutional Review Board, and Bayesian Approaches
Review
Amelia W. Maiga, Rebecca A. Snyder, Lillian S. Kao, Mehul V. Raval, Mayur B. Patel, Martin L. Blakely
Journal of Surgical Research, 25 April 2024
Introduction
…In order to address the unique challenges of designing and conducting randomized clinical trials in surgery, surgeon investigators from the Society of University Surgeons and the Association for Academic Surgery hosted a didactic session at the 2023 Academic Surgical Congress. In this paper, we summarize the key discussion points presented in this session and outline opportunities to promote the design of feasible and generalizable surgical RCTs. In particular, we will review the use of exception from informed consent (EFIC) in surgical trials, central institutional review board (IRB) review for multicenter trials, currently recommended statistical methods to increase clarity of trial findings and avoid dichotomy around the P value, and opportunities to incorporate Bayesian methods into study design and interpretation…

Participant Recruitment, Consent and Post-trial Access to Interventions
Book Chapter
Maru Mormina, Halina Suwalowska, Mira L. Schneiders
Research Ethics in Epidemics and Pandemics: A Casebook, 24 April 2024 [Springer]
Open Access
Abstract
Humanitarian emergencies, including public health crises such as epidemics, can overwhelm local resources and severely disrupt the functioning of communities and societies. Conducting research during or in the immediate aftermath of an emergency poses increased practical and ethical challenges, not least because the need to rapidly generate valuable knowledge must be constantly balanced with the principles of humanitarian assistance. This chapter provides an overview of key ethical considerations relevant to recruitment, consent and post-trial access to interventions in pandemic contexts, and proposes an “ethics in practice” approach. Research conducted during emergencies is unavoidably context – and time – sensitive, making generalized guidance difficult. The aim of this chapter is thus not to prescribe a checklist for decision-making, but to assist researchers and practitioners to reflect on and discern what constitutes ethical practice during exceptional times. In particular, public health emergencies highlight tensions that can arise between balancing the rights and interests of research participants with the health needs of the population. Careful consideration is also needed of the necessity of minimising risks and maximising benefits, including ensuring that recruitment processes are sensitive to potentially altered risk perceptions and impacts of increased vulnerability on power imbalances. The importance of establishing and maintaining trust is reviewed, particularly when asymmetries in knowledge and access to resources are heightened in complex and challenging pandemic contexts. The five case studies presented in this chapter invite readers to reflect on ethical challenges that research during public health emergencies presents, particularly in connection with processes for communicating with and recruiting participants which have been adapted in pandemic contexts; potential risks to research participants and study staff; and with the rights participants in control groups may have to access experimental products.

Individual consent in cluster randomised trials for non-pharmaceutical interventions: going beyond the Ottawa statement
Research Paper
Marissa LeBlanc, Jon Williamson, Francesco De Pretis, Jürgen Landes, Elena Rocca
Critical Public Health, 18 April 2024
Abstract
This paper discusses the issue of overriding the right of individual consent to participation in cluster randomised trials (CRTs). We focus on CRTs testing the efficacy of non-pharmaceutical interventions. As an example, we consider school closures during the COVID-19 pandemic. In Norway, a CRT was promoted as necessary for providing the best evidence to inform pandemic management policy. However, the proposal was rejected by the Norwegian Research Ethics Committee since it would violate the requirement for individual informed consent. This sparked debate about whether ethics stand in the way of evidence-based health policy, since the Norwegian Research Ethics law’s strict requirements for individual consent make it practically impossible to carry out CRTs of public health interventions. We argue that, in the case of the school closure trial, the suggested CRT would not have eliminated an epistemic gap and thus would not have justified the violation of consent rights. First, we focus on the methodological challenges to estimating quantifiable effects of school closures in the specific case of an airborne infectious disease. Second, in line with Evidential Pluralism, we highlight the value of alternative lines of evidence for informing school closure policy in a pandemic. In general, we propose that a trial requiring the waiver of participants’ consent rights must be highly likely to eliminate an epistemic gap. We elaborate on the practical aspects of this criterion and discuss the potential advantages of adding it to the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials.

Analysis of informed consent documents for compliance with ICMR guidelines for biomedical and health research
Original Article
Chaitali Ashish Chindhalore, Ganesh N. Dakhale, Snehalata V. Gajbhiye, Ashish Vijay Gupta, Shivam V Khapeka
Perspectives in Clinical Research, 8 April 2024
Abstract
Background
Ethical conduct of research depends on the voluntary expression of consent and adequate disclosure of information about the research in informed consent documents (ICDs).
Objectives
The objective of this study was to analyze ICDs of academic studies for compliance with National Ethical Guidelines for Biomedical and Health Research laid down by the Indian Council of Medical Research (ICMR) and to determine the readability of ICDs using the Flesch–Kincaid Grade Level scale and Flesch reading-ease (FRE) score.
Methodology
ICDs of academic research projects submitted during 2020–22 were retrieved from the IEC office and analyzed for compliance with ICMR 2017 guidelines. The readability of the documents was assessed by the Flesch–Kincaid Grade Level Scale and FRE score.
Results
Among 177 protocols analyzed, the most common were epidemiological studies (36.72%), followed by diagnostic studies (28.81%). Vernacular translations of ICDs were present in significantly more studies in 2022 (χ2 = 7.18, P = 0.02) as compared to 2020 and 2021. FREs score was 45.75 ± 10.76, and Flesch–Kincaid Grade Level was 8.67 ± 1.44. Content analysis of participant information sheet (PIS) revealed that significantly more PIS submitted in 2022 mentioned expected duration of participation (χ2 = 6.95, P < 0.001), benefit to patient/community (χ2 = 26.63, P < 0.001), disclosure of foreseeable risk or discomfort (χ2 = 21.72, P < 0.001), payment for participation (χ2 = 21.72, P < 0.001), and identity of research team and contact details (χ2 = 18.58, P < 0.001). Compliance score was significantly better in 2022 as compared to 2020 and 2021.
Conclusion
Gradually, ICDs became more compliant with ICMR guidelines. Still, there is scope for improvement in ICDs regarding content and readability so that patients can comprehend facts easily to make informed decisions in a real sense.

Alternative consent methods used in the multinational, pragmatic, randomised clinical trial SafeBoosC-III
Research
Maria Linander Vestager, Mathias Lühr Hansen, Gorm Greisen, SafeBoosC-III trial group
Trials, 4 April 2024
Open Access
Abstract
Background
The process of obtaining prior informed consent for experimental treatment does not fit well into the clinical reality of acute and intensive care. The therapeutic window of interventions is often short, which may reduce the validity of the consent and the rate of enrolled participants, to delay trial completion and reduce the external validity of the results. Deferred consent and ‘opt-out’ are alternative consent methods. The SafeBoosC-III trial was a randomised clinical trial investigating the benefits and harms of cerebral oximetry monitoring in extremely preterm infants during the first 3 days after birth, starting within the first 6 h after birth. Prior, deferred and opt-out consent were all allowed by protocol. This study aimed to evaluate the use of different consent methods in the SafeBoosC-III trial, Furthermore, we aimed to describe and analyse concerns or complaints that arose during the first 6 months of trial conduct.
Methods
All 70 principal investigators were invited to join this descriptive ancillary study. Each principal investigator received a questionnaire on the use of consent methods in their centre during the SafeBoosC-III trial, including the possibility to describe any concerns related to the consent methods used during the first 6 months of the trial, as raised by the parents or the clinical staff.
Results
Data from 61 centres were available. In 43 centres, only prior informed consent was used: in seven, only deferred consent. No centres used the opt-out method only, but five centres used prior and deferred, five used prior, deferred and opt-out (all possibilities) and one used both deferred and opt-out. Six centres applied to use the opt-out method by their local research ethics committee but were denied using it. One centre applied to use deferred consent but was denied. There were only 23 registered concerns during the execution of the trial.
Conclusions
Consent by opt-out was allowed by the protocol in this multinational trial but only a few investigators opted for it and some research ethics boards did not accept its use. It is likely to need promotion by the clinical research community to unfold its potential.

Human Whole-Eye Donation for Research—Optimizing Clinical Trial Informed Consent
Special Communication
Katrina A. Bramstedt
JAMA Ophthalmology, 21 March 2024
Abstract
Importance
Posthumous whole-eye (globe) donations for research lack a mechanism that reinvolves the existing ophthalmic research team of the donor unless there is a preplanned donor directive. Disconnection between the deceased and their research team equates to lost opportunities for the research team to have a longitudinal view of the eyes that have been involved in their research.
Objectives
To use the clinical trial informed consent process to create a posthumous research donation opportunity that directs the donation to the currently affiliated research team of the donors (preserving the longitudinal research experience).
Evidence Reviewed
Current globe donation pathways were reviewed. Additionally, published advice from the fields of ophthalmology, brain banking, and implantable medical devices were used as reference points.
Findings
Globe donation represents a small but valuable type of ocular donation. Globe donation for research purposes is useful for investigators performing total human eye allotransplantation clinical trials, as well as for ophthalmic drug or device researchers. Results suggest that those performing invasive eye research should include the option of posthumous globe donation in their study protocols and informed consent forms to facilitate more opportunities for the generation of scientific knowledge.
Conclusions and Relevance
The longitudinal perspective can be valuable especially for eyes that have received long-term treatment with an investigational drug or device. This article poses a research-informed consent framework for posthumous globe donation.

Contraception Requirements in Clinical Research Consent Forms: Assessing and Supporting Gender Inclusive Practices
Research Article
Tara Coffin, Erin Brower, Sharad Adekar
Journal of Empirical Research on Human Research Ethics, 11 March 2024
Abstract
Gender-diverse individuals are underserved in clinical research settings. Reliance on gendered language throughout the consent process for clinical research contributes to the marginalization of these populations. The research objective was to assess use of gender-inclusive language used to describe the contraception requirement in consent forms. We categorized and analyzed contraception language in 289 clinical trial consent forms using a deductive and summative content analysis approach. We found that 79% (n = 227) of consent forms contained gender-inclusive language, 80% (n = 231) used terms that fell under the biological sex language, and 91% (n = 264) used gendered language. No consent forms used exclusively gender-inclusive language and the majority 63% (n = 182) featuring a combination of all three language types. There were many consent forms which would have been entirely gender-inclusive language if section headings with references to biological-sex-specific contraceptives were excluded, suggesting that gender-inclusive language may be attainable with minor revisions.

Public perception of participation in low-risk clinical trials in critical care using waived consent: a Canadian national survey
Dawn Opgenorth, D’Arcy J. Duquette, Linda Tyre, Robyn Auld, Kim Crowder, Peggy Gilchrist, Paul J. Young, Sean M. Bagshaw
Canadian Journal of Anesthesia, 8 March 2024
Abstract
Purpose
The acceptability of waiver of consent for participation in clinical research in intensive care unit (ICU) settings is uncertain. We sought to survey the Canadian public to assess levels of support, comfort, and acceptability for waived consent for low-risk clinical trials.
Methods
We performed a prospective cross-sectional survey of the Canadian public aged 18 yr or older. The survey was conducted by Ipsos between 19 and 23 November 2020. The survey content was derived from a literature review and in consultation with a patient and family partnership committee. The survey focused on attitudes and beliefs on waived consent for participation in low-risk clinical trials in ICU settings. The survey contained 35 items focused on sociodemographics, general health status, participation in medical research, and levels of support and comfort with research and with waived consent. The survey used a case study of a low-risk clinical trial intervention in ICU patients. Analysis was descriptive.
Results
We included 2,000 participants, 38% of whom reported experience with ICU and 16% with medical research. Participation in medical research was more common among those with postsecondary education, those with chronic disease, and those who were employed in health care. Most (80%) would support a model of waived consent for low-risk clinical trials, citing medical benefits (36%) and low perceived risk (34%). Most (77%) were comfortable with personally participating in a low-risk clinical trial. Most (80%) believed waived consent approaches were acceptable. Half (52%) believed the waived consent process should provide information about the research and include the option of opting out. When asked whether participants should always give full informed consent, regardless of the practicality or level of risk, 74% and 72% agreed, respectively.
Conclusions
There is public support for models of waived consent for participation in low-risk pragmatic clinical trials in ICU settings in Canada; however, this is not universal. This information can inform and guide education, ethics, policy, and legal discussion on consent models.

Public support for and concerns regarding pediatric dose optimization for seizures in emergency medical services: An exception from informed consent (EFIC) trial
Ward CE, Adelgais KM, Holsti M, Jacobsen KK, Simon HK, Morris CR, Gonzalez VM, Lerner G, Ghaffari K, VanBuren JM, Lerner EB, Shah MI
Academic Emergency Medicine, 7 March 2024
Abstract
Background
Federal regulations allow exception from informed consent (EFIC) to study emergent conditions when obtaining prospective consent is not feasible. Little is known about public views on including children in EFIC studies. The Pediatric Dose Optimization for Seizures in EMS (PediDOSE) trial implements age-based, standardized midazolam dosing for pediatric seizures. The primary objective of this study was to determine public support for and concerns about the PediDOSE EFIC trial. The secondary objective was to assess how support for PediDOSE varied by demographics.
Methods
We conducted a mixed-methods study in 20 U.S. communities. Participants reviewed information about PediDOSE before completing an online survey. Descriptive data were generated. Univariable and multivariable logistic regression analysis identified factors associated with support for PediDOSE. Reviewers identified themes from free-text response data regarding participant concerns.
Results
Of 2450 respondents, 79% were parents/guardians, and 20% had a child with previous seizures. A total of 96% of respondents supported PediDOSE being conducted, and 70% approved of children being enrolled without prior consent. Non-Hispanic Black respondents were less likely than non-Hispanic White respondents to support PediDOSE with an adjusted odds ratio (aOR) of 0.57 (95% CI 0.42-0.75). Health care providers were more likely to support PediDOSE, with strongest support among prehospital emergency medicine clinicians (aOR 5.82, 95% CI 3.19-10.62). Age, gender, parental status, and level of education were not associated with support of PediDOSE. Common concerns about PediDOSE included adverse effects, legal and ethical concerns about enrolling without consent, and potential racial bias.
Conclusions
In communities where this study will occur, most respondents supported PediDOSE being conducted with EFIC and most approved of children being enrolled without prior consent. Support was lowest among non-Hispanic Black respondents and highest among health care providers. Further research is needed to determine optimal ways to address the concerns of specific racial and ethnic groups when conducting EFIC trials.

Ethical Challenges with the Informed Consent Process in Pediatric Research Studies
Thabit S. Alotaibi
Medical Archives, 2024; 78(1) pp 65-67
Abstract
Background
Informed Consent (IC) is crucial in pediatric research, aligning with the National Research Act of 1974 and the Belmont Report’s principles. Current regulations, particularly 45 CFR 46, provide additional safeguards for children in research.
Objective
This article explores ethical challenges in pediatric research IC, drawing from PubMed literature and regulatory guidelines to understand historical context, legislative milestones, and contemporary issues.
Methods
A literature review, primarily sourced from PubMed, informed the examination of pediatric research and IC, referencing guidelines from the American Academy of Pediatrics and regulations from the FDA and HHS.
Results
The study underscores the need for increased pediatric research due to the prevalence of drugs studied on adults. Despite legislative efforts like the FDAMA and Pediatric Research Equity Act, ethical challenges persist in obtaining IC in pediatric studies.
Conclusion
Pediatric research necessitates nuanced IC approaches, involving parents, guardians, and children. Ethical challenges such as coercion and compensation require attention, with recommendations emphasizing guideline adherence and increased public engagement for trust-building and pediatric health advancement.