Quality of Informed Consent in Phase III Clinical Trials in Portugal: The Participants’ Perspective
Pedro L. Ferreira, Ana Barradas, Inês Ribeiro
Acta Médica Portuguesa, 19 July 2024
Abstract
Introduction
Some studies show that participants do not always fully understand the informed consent form (ICF), which is one of the reasons for dropouts. This study aimed to adapt the Quality of Informed Consent (QuIC) questionnaire into a valid instrument to be applied to the Portuguese population and to measure its reliability and validity in the Portuguese population, by applying it to a sample of participants in controlled trials.
Methods
The QuIC questionnaire was developed to assess the quality of informed consent in clinical trials and consists of two parts, addressing both the objective (part A) and the subjective (part B) understanding. After being translated and validated into Portuguese, it was implemented in 100 cardiac participants of phase III clinical trials in a University Hospital Center.
Results
The QuIC-PT questionnaire showed excellent stability over time and good validity. All patients evaluated their participation and their health positively and recognized the main purpose of the clinical trial. Almost all participants understood their role in helping future patients and the purpose of the trial and realized that, by signing the ICF, they were participating in a clinical trial. However, none of them knew that their experimental treatment was not proven to be the best alternative for their condition.
Conclusion
The QuIC-PT questionnaire seems to be a valid and useful instrument to evaluate the participants’ understanding of the ICF. In this study, we found that some concepts, like ‘study protocol’ or ‘randomization’, were not well understood by participants when signing the ICF, especially by participants with lower education levels. They also believed that the experimental intervention would solve their health condition. Greater awareness about the importance of the informed consent process and ICF is necessary so that participants can fully understand the protocol, especially the risks involved, and their rights as participants.

Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design A scoping review
Original Research
Alain Amstutz, Christof M. Schönenberger, Benjamin Speich, Alexandra Griessbach, Johannes M. Schwenke, Jan Glasstetter, Sophie James, Helena M. Verkooijen, Beverley Nickolls, Clare Relton, Lars G. Hemkens, Frédérique Chammartin, Felix Gerber, Niklaus D. Labhardt, Stefan Schandelmaier, Matthias Briel
Journal of Clinical Epidemiology, 19 July 2024
Open Access
Abstract
Objective
Trials within Cohorts (TwiCs) is a pragmatic design approach that may overcome frequent challenges of traditional randomized trials such as slow recruitment, burdensome consent procedures, or limited external validity. This scoping review aims to identify all randomized controlled trials using the TwiCs design and to summarize their design characteristics, ways to obtain informed consent, output, reported challenges and mitigation strategies.
Study design and setting
Systematic search of Medline, Embase, Cochrane, trial registries and citation tracking up to December 2022. TwiCs were defined as randomized trials embedded in a cohort with post-randomization consent for the intervention group and no specific post-randomization consent for the usual care control group. Information from identified TwiCs were extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to non-uptake of interventions and informed consent procedure.
Results
We identified a total of 46 TwiCs conducted between 2005 and 2022 in 14 different countries by a handful of research groups. The most common medical fields were oncology (11/46; 24%), infectious diseases (8/46;17%), and mental health (7/46; 15%). A typical TwiCs was investigator-initiated (46/46;100%), publicly funded (36/46; 78%), and recruited outpatients (27/46; 59%). Excluding eight pilot trials, only 16/38 (42%) TwiCs adjusted their calculated sample size for non-uptake of the intervention, anticipating a median non-uptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for non-uptake. Regarding informed consent, we observed three patterns: 1) three separate consents for cohort participation, randomization, and intervention (17/46; 37%); 2) combined consent for cohort participation and randomization and a separate intervention consent (10/46; 22%); and 3) consent only for cohort participation and intervention (randomization consent not mentioned; 19/46; 41%).
Conclusions
Existing TwiCs are globally scattered across a few research groups covering a wide range of medical fields and interventions. Despite the potential advantages, the number of TwiCs remains small. The variability in consent procedures and the possibility of substantial non-uptake of the intervention warrants further her research to guide the planning, implementation, and analysis of TwiCs.

Waiving the consent requirement to mitigate bias in observational precision medicine research
Comment
Ruifeng Song
International Journal for Equity, 18 July 2024
Open Access
Abstract
Consent bias is a type of selection bias in biomedical research where those consenting to the research differ systematically from those not consenting. It is particularly relevant in precision medicine research because the complexity of these studies prevents certain subgroups from understanding, trusting, and consenting to the research. Because consent bias distorts research findings and causes inequitable distribution of research benefits, scholars propose two types of schemes to reduce consent bias: reforming existing consent models and removing the consent requirement altogether. This study explores the possibility of waiving consent in observational studies using existing data, because they involve fewer risks to participants than clinical trials if privacy safeguards are strengthened. It suggests that data protection mechanisms such as security enhancement and data protection impact assessment should be conducted to protect data privacy of participants in observational studies without consent.

Editor’s note: In reflecting on the argument as presented in the abstract, we are reaching out to explore and assess further in dialogue with the author.

Coerced consent in clinical research: study protocol for a randomized controlled trial
Study Protocol
Connor T. A. Brenna, Nancy Walton, Melanie Cohn, Urooj Siddiqui, Ella Huszti, Richard Brull
Trials, 4 July 2024
Open Access
Abstract
Background
Despite the low-risk nature of participation in most clinical anesthesia trials, subject recruitment on the same day as surgery is often restricted due to the concerns of researchers and local research ethics boards that same-day consent may not afford adequate time and opportunity for patients to weigh and make decisions, as well as perceptions of patient vulnerability immediately prior to surgery that could impact the voluntary nature and the rigor of the informed consent process. However, specialties such as anesthesiology, critical care, interventional radiology, and emergency medicine have a varied pattern of practice and patient acquaintance that does not typically afford the luxury of time or, in many cases, advance consent for participation in research. Indeed, the initial encounter between anesthesiologists and patients undergoing elective procedures routinely occurs on the day of surgery. Concerns of coercion related to same-day consent for clinical anesthesia research trials have not been borne out in the literature, and represent a significant obstacle to clinical researchers, as well as to the patients who are denied opportunities for potential benefit through participation in research studies.
Methods
We describe the protocol for a prospective randomized controlled trial examining the voluntariness of patient consent, solicited either in advance of surgery or on the same day, to participate in an anesthesia research study at Women’s College Hospital [Toronto, Canada]. One hundred fourteen patients scheduled to undergo ambulatory anterior cruciate ligament repair facilitated by general anesthesia with an adductor canal block will be randomized for recruitment either (a) in the pre-operative assessment clinic before the day of surgery or (b) on the day of surgery, to be approached for consent to participate in a fabricated research study of adjunct medications in adductor canal blocks. Regardless of allocation, patients in both groups will receive the same routine standard of care and will complete a post-operative questionnaire to signal perceptions of undue influence in the process of providing informed consent for the fabricated trial.
Discussion
This study will inform trial design and practice guidelines surrounding the amount of time patients ought to be afforded in order to make durable decisions to participate (or not) in clinical research studies. This is expected to impact trial recruitment in a variety of clinical settings where researchers have only brief opportunities to interface with patients.

Interactive Media-Based Approach for an Exception From Informed Consent Trial Involving Patients With Trauma
Shannon W. Stephens, Christy Carroll-Ledbetter, Sarah Duckert, Tanner Coffman, Margaret Nelson, Karen N. Brown, Joel Rodgers, Russell L. Griffin, Amy Suen, Jeremy Casey, Steven R. Sloan, Brahm Goldstein, Adam Joseph McClintock, Sara F. Goldkind, Luke Gelinas, Amanda E. Higley, Bellal A. Joseph, John B. Holcomb, Jan O. Jansen
JAMA Surgery, 3 July 2024
Abstract
Importance
Exception From Informed Consent (EFIC) research requires community consultation (CC) and public disclosure (PD). Traditional methods of conducting CC and PD are slow, expensive, and labor intensive.
Objective
To describe the feasibility and reach of a novel interactive, media-based approach to CC and PD and to identify the similarities and differences between trial sites in website views, survey responses, online community forum attendance, and opt-out requests.
Design, Setting, and Participants
This survey study analyzed the CC and PD campaigns conducted for the TAP trial (Evaluation of BE1116 in Patients With Traumatic Injury and Acute Major Bleeding to Improve Survival), an EFIC trial of the early administration of prothrombin complex concentrate in patients with trauma. The CC and PD campaigns consisted of social media advertisements, linked websites, community surveys, and online community forums. These activities were coordinated from a central site and approved by a central institutional review board. This study focused on the first 52 of 91 TAP trial sites (level I trauma centers) in the US to have completed their CC and PD campaigns. Community members in the catchment areas of the participating trauma centers were targeted. Data analysis was conducted between October 2023 and February 2024.
Exposure
Social media advertisements, surveys, and online community meetings conducted as part of the CC and PD campaign for the TAP trial.
Main Outcomes and Measures
Social media campaign reach and engagement, web page views, survey results, online community forum attendance, and opt-out requests.
Results
Fifty-two trial sites were approved for participant enrollment. Social media advertisements were displayed 92 million times, reaching 11.8 million individuals. The median (IQR) number of people reached in each location was 210 317 (172 068-276 968). Site-specific websites were viewed 144 197 times (median [IQR] viewings per site, 2984 [1267-4038]). A total of 17 206 fully or partly completed surveys were received, and survey respondents had a median (IQR) age of 40.1 (15-65) years and included 10 444 females (60.7%). Overall, 60.6% survey respondents said they would want to be entered into the trial even if they could not give consent, 87.7% agreed that emergency care research was necessary, and 88.0% agreed that the TAP trial should be conducted in their community. Online community forums were attended by a median (IQR) number of 38 (20-63) people. Four opt-out requests were received.
Conclusions and Relevance
The interactive media-based approach to CC and PD for the ongoing TAP trial showed the feasibility and benefits of executing an efficient, coordinated, centrally run series of locally branded and geographically targeted CC and PD campaigns for a large EFIC study.

Exception From Informed Consent—A Model for Donor Intervention Research
Invited Commentary
Anji E. Wall, Giuliano Testa
JAMA Surgery, 3 July 2024
Abstract
In their article “Interactive Media-Based Approach for an Exception From Informed Consent Trial Involving Patients With Trauma,” Stephens and colleagues demonstrate the feasibility of a multicenter community consultation and public disclosure campaign for exception for informed consent for the Trauma and Prothrombin Complex Concentrate (TAP) trial.1 The unique interactive media-based approach resulted in widespread reach to the community through social media and active community participation through surveys, virtual forums, and opt-out requests. Over 50 level 1 trauma centers adopted this approach, which demonstrated the feasibility of a centrally run, locally branded, and geographically targeted campaign.

The ethical value of consulting community members in non-emergency trials conducted with waivers of informed consent for research
Emily A Largent, Steven Joffe, Neal W Dickert, Stephanie R Morain
Clinical Trials, 25 June 2024
Abstract
There is growing interest in using embedded research methods, particularly pragmatic clinical trials, to address well-known evidentiary shortcomings afflicting the health care system. Reviews of pragmatic clinical trials published between 2014 and 2019 found that 8.8% were conducted with waivers of informed consent; furthermore, the number of trials where consent is not obtained is increasing with time. From a regulatory perspective, waivers of informed consent are permissible when certain conditions are met, including that the study involves no more than minimal risk, that it could not practicably be carried out without a waiver, and that waiving consent does not violate participants’ rights and welfare. Nevertheless, when research is conducted with a waiver of consent, several ethical challenges arise. We must consider how to: address empirical evidence showing that patients and members of the public generally prefer prospective consent, demonstrate respect for persons using tools other than consent, promote public trust and investigator integrity, and ensure an adequate level of participant protections. In this article, we use examples drawn from real pragmatic clinical trials to argue that prospective consultation with representatives of the target study population can address, or at least mitigate, many of the ethical challenges posed by waivers of informed consent. We also consider what consultation might involve to illustrate its feasibility and address potential objections.

Consent Form Reporting on ClinicalTrials.Gov, 2013-2023
Research Letter
Sydney A. Axson, Reshma Ramachandran, Alexa Lisenby, Nicholas A. Giordano
JAMA Open, 21 June 2024; 7(6)
Introduction
Informed consent documentation is legally, ethically, and scientifically imperative for research and provides prospective trial participants key study information. Historically, consent documents have been difficult to obtain and not consistently publicly available. As of July 21, 2019, and after a 2-year voluntary period, the revised Common Rule required select federally funded interventional trials to publicly post consent forms no later than 60 days after the last participant visit. The revision intends to increase research transparency and inform consent development. Although transparency efforts addressing trial registrations and results are well studied, less is known about public availability of consent forms in the context of the revised rule’s recent implementation. This cross-sectional analysis examined National Institutes of Health (NIH)–funded trial consent form availability on ClinicalTrials.gov.