Refusal rates and waivers of informed consent in pragmatic and comparative effectiveness RCTs: A systematic review
Lisa Y. Lin, Nicole Jochym, Jon F. Merz
Contemporary Clinical Trials, May 2021; 104
Abstract
Background
Pragmatic and comparative effectiveness randomized controlled trials (RCTs) aim to be highly generalizable studies, with broad applicability and flexibility in methods. These trials also address recruitment issues by minimizing exclusions. The trials may also appeal to potential subjects because of lower risk and lower burdens of participation. We sought to examine rates of refusal and uses of waivers of informed consent in pragmatic and comparative effectiveness RCTs.
Methods
A systematic review of pragmatic and comparative effectiveness RCTs performed wholely or in part in the United States and first published in 2014 and 2017.
Results
103 studies involving 105 discrete populations were included for review. Refusal data was collected for 71 RCTs. Overall, studies reported an average rate of 31.9% of potential subjects refused participation; on an individual basis, 38.4% of people asked to take part refused at some point during recruitment. 23 trials (22%) were performed, at least in part, with a waiver of informed consent, 7 (30%) of which provided any form of notice to subjects.
Conclusions
Overall refusal rates for pragmatic and comparative effectiveness RCTs appear roughly the same as other types of research, with studies reporting about a third of people solicited for participation refuse. Moreover, informed consent was waived in 22% (95% Binomial exact Confidence Interval 13.9–30.5%) of the trials, and further study is needed to understand when waivers are justified and when notice should be provided.

Patients Acceptance and Comprehension to Written and Verbal Consent (PAC-VC)
Research Article
Rabia Kashur, Justin Ezekowitz, Shane Kimber, Robert Welsh
BMC Medical Ethics, 2 March 2021
Open Access
Abstract
Background
Acute myocardial infarction (AMI) research is challenging as it requires enrollment of acutely ill patients. Patients are generally in a suboptimal state for providing informed consent. Patients’ understanding to verbal assents have not been previously examined in AMI research. Patients Acceptance and Comprehension to Written and Verbal Consent (PAC-VC) compared patients’ understanding and attitudes to verbal and written consents in AMI RCTs.
Methods
PAC-VC recruited patients from 3 AMI trials using both verbal N=12 and written N=6 consents. We compared patients’ understanding using two survey questionnaires. The first questionnaire used open ended questions with multiple choice answers. The second questionnaire used a 5-point Likert scale to measure patients understanding and attitudes to the consent process. Overall answers average scores were categorized into three groups: Adequate understanding (71-100) %, Partial understanding (41-70)% and Inadequate understanding (0-40)%.
Results
Responses showed patients with verbal assent had adequate understanding to most components of iinformed consent, close to those of written consent. Most patients did not read written information entirely and believed that it is not important to make a final decision. Patients favoured to have written information be part of the consent but not necessarily presented during the initial consent process. Patients felt less pressured in the verbal assent arm than those of written consent.
Conclusion
Patients had adequate understanding to most components of verbal assent and comparable to those of written consent. Utilizing verbal assents in the acute care setting should be further assessed in larger trials.

Distinctive aspects of consent in pilot and feasibility studies
Original Paper
Julius Sim
Journal of Evaluation in Clinical Practice, 24 February 2021
Open Access
Abstract
Prior to a main randomized clinical trial, investigators often carry out a pilot or feasibility study in order to test certain trial processes or estimate key statistical parameters, so as to optimize the design of the main trial and/or determine whether it can feasibly be run. Pilot studies reflect the design of the intended main trial, whereas feasibility studies may not do so, and may not involve allocation to different treatments. Testing relative clinical effectiveness is not considered an appropriate aim of pilot or feasibility studies. However, consent is no less important than in a main trial as a means of morally legitimizing the investigator’s actions. Two misperceptions are central to consent in clinical studies—therapeutic misconception (a tendency to conflate research and therapy) and therapeutic misestimation (a tendency to overestimate possible benefits and/or underestimate possible harms associated with participation). These phenomena may take a distinctive form in pilot and feasibility studies, owing to potential participants’ likely prior unfamiliarity with the nature and purposes of such studies. Thus, participants may confuse the aims of a pilot or feasibility study (developing or optimizing trial design and processes) with those of a main trial (testing treatment effectiveness) and base consent on this misconstrual. Similarly, a misunderstanding of the ability of pilot and feasibility studies to provide information that will inform clinical care, or the underdeveloped nature of interventions included in such studies, may lead to inaccurate assessments of the objective possibility of benefit, and weaken the epistemic basis of consent accordingly. Equipoise may also be particularly challenging to grasp in the context of a pilot study. The consent process in pilot and feasibility studies requires a particular focus, and careful communication, if it is to carry the appropriate moral weight. There are corresponding implications for the process of ethical approval.

Model Operational Procedures for the Implementation and Review of NIH Sponsored Multicenter Clinical Trials with Exception from Informed Consent (EFIC) for Emergency Research
SIREN Clinical Coordinating Center
Version 1, January 2021
Open Access
Introduction
    The purpose of this document is to provide a model process and procedures that can be used as starting point for implementation of clinical trials using Exception from Informed Consent for Emergency Research (EFIC) in NIH funded multicenter clinical trials. The process and procedures described can and must be adapted to the specific needs and details of any future trials. The materials provided were developed and informed by both thorough review of the accumulated scholarship related to EFIC, and other lessons learned through practical shared experiences of prior NIH funded emergency care researchers.
This document is intended to be a useful, practical, and tested peer-to-peer tool for future investigators in this field. It is not intended to be a definitive guideline for application of the EFIC regulations, and should NOT be interpreted as any form of regulatory guidance. Regulatory guidance is available from FDA. This document does not represent the only way to implement Exception from Informed Consent, and may not be applicable or optimal for EFIC studies that differ from those for which this document was created. This document is intended to be open access, and shared through a Creative Commons Attribution-NonCommercial (CC BY-NC) license that lets others adapt, and build upon the work non-commercially. New works must acknowledge the source materials and the NIH and be non-commercial. The derivative works do not have be licensed on the same terms.

Nano-drug Clinical Trials: Informed Consent and Risk Management Through Blockchain
Yousef Haik, Ilias Bantekas
Pittsburgh Journal of Technology Law & Policy, 2021
Open Access
Abstract
Drug bearing nano-shells that can be utilized for targeted drug delivery have been shown to enhance the therapeutic index by increasing the drug concentration in diseased tissue and reducing the toxicity in normal tissue. The controllability of the drug bearing shell size provides predictability measure for the amount of drug payload per shell which improves the administration of the therapeutic dose.  The FDA approved different formulations for clinical use in metastatic and recurrent breast cancer, among other diseases.  At the moment, some of these formulations are the subject of international clinical trials.  Informed consent is legally mandated in administering drug bearing nano-shells.  The risks of the new formulations, as with all new technologies, are not well known and continue to be a subject of intensive research, thus exacerbating the existing informed consent legal issues, thus exacerbating the existing informed consent legal issues.  This short essay focuses on proposing a framework to mitigate liabilities administering a new formulation on nano-enabled drug carriers particularly when uncertainties of the benefits and damages are not fully known.