Details of risk–benefit communication in informed consent documents for phase I/II trials
Research Article
Hannes Kahrass, Sabine Bossert, Christopher Schürmann, Daniel Strech
Clinical Trials, 24 November 2020
Abstract
Background
Informed consent documents for clinical studies should disclose all reasonably foreseeable risks and benefits. Little guidance exists on how to navigate the complexities of risk–benefit communication, especially in early clinical research. Practice-oriented development of such guidance should be informed by evidence on what and how details of risks and benefits are currently communicated.
Method
We surveyed the responsible parties of phase I/II trials registered in ClinicalTrials.gov that started 2007 or later and completed between 2012 and 2016 to sample informed consent documents from a broad spectrum of early phase clinical trials. Based on an assessment matrix, we qualitatively and quantitatively assessed the informed consent documents for details of risk–benefit communication.
Results
The risk–benefit communication in the 172 informed consent documents differed substantially in several regards. The outcome, extent, and likelihood of health risks, for example, were described in 83%, 32%, and 63% of the informed consent documents. Only 45% of informed consent documents specified the outcome of mentioned health benefits, and the extent and likelihood of health benefits were never specified. From those informed consent documents reporting risk likelihoods, only 57% added frequency numbers to words such as “common” or “rare,” and even in these cases, we found strong variations for presented frequency ranges. Substantial heterogeneity also exists for how informed consent documents communicate other risk and benefit types and related safeguards.
Conclusion
Our study points to several shortcomings and heterogeneities in how informed consent documents communicate risks and benefits to potential research participants. Health risks, for example, should be specified with frequency numbers, and health benefits should be specified at least by mentioning their outcomes. Further demand for research and policy development is needed to harmonize risk–benefit communication and to clarify ways to specify the likelihood of health benefits.

Differences in demographics and outcomes based on method of consent for a randomised controlled trial on heat loss prevention in the delivery room
Original Research
Sunita Vohra, Maureen Reilly, Valeria E Rac, Zafira Bhaloo, Denise Zayak, John Wimmer, Michael Vincer, Karla Ferrelli, Alex Kiss, Roger Soll, Michael Dunn
Archives of Disease in Childhood – Fetal and Neonatal Edition, 24 November 2020
Abstract
Objective
Informed consent is standard in research. International guidelines allow for research without prior consent in emergent situations, such as neonatal resuscitation. Research without prior consent was incorporated in the Vermont Oxford Network Heat Loss Prevention Trial. We evaluated whether significant differences in outcomes exist based on the consent method.
Design
Subgroup analysis of infants enrolled in a randomised controlled trial conducted from 2004 to 2010.
Setting
A multicentre trial with 38 participating centres.
Participants
Infants born 24–27 weeks of gestation. 3048 infants assessed, 2231 excluded due to fetal congenital anomalies, failure to obtain consent or gestation less than 24 weeks. 817 randomised, 4 withdrew consent, total of 813 analysed.
Main outcome measure
The difference in mortality between consent groups.
Results
No significant differences were found in mortality at 36 weeks (80.2%, 77.4%, p=0.492) or 6 months corrected gestational age (80.7%, 79.7%, p=0.765). Infants enrolled after informed consent were more likely to have mothers who had received antenatal steroids (95.2%, 84.0%, p<0.0001). They also had significantly higher Apgar scores at 1 (5.0, 4.4, p=0.019), 5 (7.3, 6.7, p=0.025) and 10 min (7.5, 6.3, p=0.0003).
Conclusions and relevance
Research without prior consent resulted in the inclusion of infants with different baseline characteristics than those enrolled after informed consent. There were no significant differences in mortality. Significantly higher Apgar scores in the informed consent group suggest that some of the sicker infants would have been excluded from enrolment under informed consent. Research without prior consent should be considered in neonatal resuscitation research.

A systematic review of risk communication in clinical trials: How does it influence decisions to participate and what are the best methods to improve understanding in a trial context?
Maeve Coyle, Katie Gillies
PLOS One, 16 November 2020
Open Access
Abstract
Background
Effective risk communication is challenging. Ensuring potential trial participants’ understand ‘risk’ information presented to them is a key aspect of the informed consent process within clinical trials, yet minimal research has looked specifically at how to communicate probabilities to support decisions about trial participation. This study reports a systematic review of the literature focusing on presentation of probabilistic information or understanding of risk by potential trial participants.
Methods
A search strategy for risk communication in clinical trials was designed and informed by systematic reviews of risk communication in treatment and screening contexts and supplemented with trial participation terms. Extracted data included study characteristics and the main interventions/findings of each study. Explanatory studies that investigated the methods for presenting probabilistic information within participant information leaflets for a clinical trial were included, as were interventions that focused on optimising understanding of probabilistic information within the context of a clinical trial.
Results
The search strategy identified a total of 4931 studies. Nineteen papers were selected for full text screening, and seven studies included. All reported results from risk communication studies that aimed to support potential trial participants’ decision making set within hypothetical trials. Five of these were randomised comparisons of risk communication interventions, and two were prospectively designed, non-randomised studies. Study interventions focused on probability presentation, risk framing and risk interpretation with a wide variety of interventions being evaluated and considerable heterogeneity in terms of outcomes assessed. Studies show conflicting findings when it comes to how best to present information, although numerical, particularly frequency formats and some visual aids appear to have promise.
Conclusions
The evidence base surrounding risk communication in clinical trials indicates that there is as yet no clear optimal method for improving participant understanding, or clear consensus on how it affects their willingness to participate. Further research into risk communication within trials is needed to help illuminate the mechanisms underlying risk perception and understanding and provide appropriate ways to present and communicate risk in a trial context so as to further promote informed choices about participation. A key focus for future research should be to investigate the potential for learning in the evidence on risk communication from treatment and screening decisions when applied to decisions about trial participation.

Consent Forms and Procedures [BOOK CHAPTER]
Ann-Margret Ervin, Joan B. Cobb Pettit
Principles and Practice of Clinical Trials
Springer Nature, 11 November 2019
Open Access
Abstract
Obtaining the informed consent of a participant is a prerequisite for enrollment in a clinical trial. In the United States, federal regulations provide the framework for establishing informed consent with additional protections for persons considered vulnerable due to incarceration, illiteracy, or other condition. Investigators are tasked with providing sufficient information about the research to satisfy the ethical and regulatory requirements while communicating it in a manner that maximizes the participant’s ability to make an informed decision regarding study enrollment. There are clinical trial design features that are essential to include in the consent form with care to describe topics such as randomization, allocation ratio, and masking in a manner understood by the lay public. The informed consent discussion should continue throughout the course of the trial as informally reaffirming the participant’s willingness to continue participation and reconsenting them when there are significant changes to the study protocol are important considerations for providing truly informed consent.

Loopholes in the Research Ethics System? Informed Consent Waivers in Cluster Randomized Trials with Individual‐Level Intervention
Article
Alex John London, Monica Taljaard, Charles Weijer
Ethics & Human Research, 2 November 2020
Abstract
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.

Nocebo effects by providing informed consent in shared decision making? Not necessarily: a randomized pilot-trial using an open-label placebo approach
Research Article
Fabian Holzhüter, Johannes Hamann
BMC Medical Ethics, 14 October 2020; 21(97)
Open Access
Abstract
Background
Thorough information of the patient is an integral part of the process of shared decision making. We aimed to investigate if detailed information about medication may induce nocebo (or placebo) effects.
Methods
We conducted a randomized, single-blind, pilot-study including n = 51 psychiatric in-patients aged between 18 and 80 years with a depressive disorder and accompanying sleeping disorders. In the intervention group we provided thorough information about adverse effects, while the control group received only a simple consent procedure. In both groups, patients received an open-label placebo pill instead of their sleeping medication.
Results
No statistically significant differences between the intervention group and the control group were found regarding the main outcome parameter (a visual analogue scale indicating impairment by the new pill).
Conclusion
In this study, we were not able detect an effect of informed consent vs. simple consent on the emergence of placebo or nocebo effects. This finding is contrary to most assumptions and publications about this topic.

Neuropsychological validation of a brief quiz to examine comprehension of consent information in observational studies of substance users
Research Article
Aldebarán Toledo-Fernández, Ricardo Sánchez-Domínguez, Luis Villalobos-Gallegos, Alejandro Pérez-López, Alan Macías-Flores, Rodrigo Marín-Navarrete
Ethics & Behaviour, 12 October 2020
Abstract
The objective of this study was to determine the accuracy of a brief informed consent quiz (ICQ) to detect consent comprehension in individuals with cognitive impairment (as a proxy of incomprehension) and to explore the degree to which cognitive domains and recent substance use, independently, predict comprehension. We performed a secondary analysis of two cross-sectional studies in individuals with substance use disorders. The ICQ total score was used as the index test and the Montreal Cognitive Assessment (MoCA) as reference standard in receiver operating characteristic curves. Two independent multiple binary logistic regression models were performed using cognitive domains and days of recent substance use as predictors of ICQ outcome. We analyzed data from 215 and 251 participants, respectively. The ICQ showed moderate accuracy for major cognitive impairment (MoCA ≤ 21) (area under the curve ~ 77) and lower accuracy for mild impairment (MoCA ≤ 24) (area under the curve ~ 65). Optimal cutoff score was set at 10 points or less for detecting comprehension difficulty. Lower scores in Short-Term Memory, Attention, Language, and Orientation increased the probability of failing the ICQ. A procedure including both the ICQ and cognitive screening measure could improve the accuracy of consent comprehension assessments.

Researchers’ views on, and experiences with, the requirement to obtain informed consent in research involving human participants: a qualitative study
Research Article
Antonia Xu, Melissa Therese Baysari, Sophie Lena Stocker, Liang Joo Leow, Richard Osborne Day & Jane Ellen Carland
BMC Medical Ethics, 2 October 2020; 21(93)
Open Access
Abstract
Background
Informed consent is often cited as the “cornerstone” of research ethics. Its intent is that participants enter research voluntarily, with an understanding of what their participation entails. Despite agreement on the necessity to obtain informed consent in research, opinions vary on the threshold of disclosure necessary and the best method to obtain consent. We aimed to investigate Australian researchers’ views on, and their experiences with, obtaining informed consent.
Methods
Semi-structured interviews were conducted with 23 researchers from NSW institutions, working in various fields of research. Interviews were analysed and coded to identify themes.
Results
Researchers reported that consent involved information disclosure, understanding and a voluntary decision. They emphasised the variability of consent interactions, which were dependent on potential participants’ abilities and interests, study complexity and context. All researchers reported providing written information to potential participants, yet questioned the readability and utility of this information. The majority reported using signed consent forms to ‘operationalise’ consent and reported little awareness of, and lack of support in implementing more dynamic informed consent procedures, such as verbal informed consent, that was fit for the purposes of their studies. Views on Human Research Ethics Committees (HRECs) varied. Some reported inconsistent, arduous inputs on the information form and consent process. Others expressed reliance on HRECs for guidance, viewing them as institutional safeguards.
Conclusions
This study highlights the importance of transparent relationships, both between researchers and participants, and between researchers and HRECs. Where the relationship with study participants was reported as more robust, researchers felt that they were better able to ensure participants made better, more informed decisions. Where the relationship with HRECs was reported as more robust, researchers were more likely to view them as institutional safeguards, rather than as bureaucratic hindrances. Conscientious and mindful researchers are paramount to ensuring the procedure accommodates individual requirements. This study advocates that when designing ethical informed consent practices, researchers should be integrated as autonomous players with a positive input on the process, rather than, in the worst case, predatory recruiters to be curtailed by information forms and oversight.

High-impact RCTs without prospective informed consent: a systematic review
Review
Roma Dhamanaskar, Jon F Merz
Journal of Investigative Medicine, 1 October 2020
Abstract
The prevalence of randomized controlled trials (RCTs) performed without fully informed prospective consent from subjects is unknown. We performed this study to estimate the prevalence of high-impact RCTs performed without informed consent from all subjects and examine whether such trials are becoming more prevalent. We performed a systematic review of English-language RCTs published from 2014 through 2018 identified in Scopus and sorted to identify the top 100 most highly cited RCTs each year. Text search of title and abstract included terms randomized controlled or clinical trial and spelling variants thereof, and excluded metaanalyses and systematic reviews. We independently identified the most highly cited RCTs based on predefined criteria and negotiated to agreement, then independently performed keyword searches, read, abstracted and coded information regarding informed consent from each paper and again negotiated to agreement. No quality indicators were assessed. We planned descriptive qualitative analysis and appropriate quantitative analysis to examine the prevalence and characteristics of trials enrolling subjects with other than fully informed prospective consent. We find that 44 (8.8%, binomial exact 95% CI 6.5% to 11.6%) of 500 high-impact RCTs did not secure informed consent from at least some subjects. The prevalence of such trials did not change over the 5 years (OR=1.09, z=0.78, p=0.44). A majority (66%) of the trials involved emergency situations, and 40 of 44 (90.9%) of the trials involved emergency interventions, pragmatic designs, were cluster randomized, or a combination of these factors. A qualitative analysis explores the methods of and justifications for waiving informed consent in our sample of RCTs.

Implementation of Electronic Informed Consent in Biomedical Research and Stakeholders’ Perspectives: Systematic Review
Review
Evelien De Sutter, Drieda Zaçe, Stefania Boccia, Maria Luisa Di Pietro, David Geerts, Pascal Borry, Isabelle Huys
Journal of Medical Research, October 2020; 22(10)
Open Access
Abstract
Background
Informed consent is one of the key elements in biomedical research. The introduction of electronic informed consent can be a way to overcome many challenges related to paper-based informed consent; however, its novel opportunities remain largely unfulfilled due to several barriers.
Objective
We aimed to provide an overview of the ethical, legal, regulatory, and user interface perspectives of multiple stakeholder groups in order to assist responsible implementation of electronic informed consent in biomedical research.
Methods
We conducted a systematic literature search using Web of Science (Core collection), PubMed, EMBASE, ACM Digital Library, and PsycARTICLES. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were used for reporting this work. We included empirical full-text studies focusing on the concept of electronic informed consent in biomedical research covering the ethical, legal, regulatory, and user interface domains. Studies written in English and published from January 2010 onward were selected. We explored perspectives of different stakeholder groups, in particular researchers, research participants, health authorities, and ethics committees. We critically appraised literature included in the systematic review using the Newcastle-Ottawa scale for cohort and cross-sectional studies, Critical Appraisal Skills Programme for qualitative studies, Mixed Methods Appraisal Tool for mixed methods studies, and Jadad tool for randomized controlled trials.
Results
A total of 40 studies met our inclusion criteria. Overall, the studies were heterogeneous in the type of study design, population, intervention, research context, and the tools used. Most of the studies’ populations were research participants (ie, patients and healthy volunteers). The majority of studies addressed barriers to achieving adequate understanding when using electronic informed consent. Concerns shared by multiple stakeholder groups were related to the security and legal validity of an electronic informed consent platform and usability for specific groups of research participants.
Conclusions
Electronic informed consent has the potential to improve the informed consent process in biomedical research compared to the current paper-based consent. The ethical, legal, regulatory, and user interface perspectives outlined in this review might serve to enhance the future implementation of electronic informed consent.