Advances and challenges in conducting ethical trials involving populations lacking capacity to consent: A decade in review
Victoria Shepherd
Contemporary Clinical Trials, August 2020; 95
Abstract
Informed consent is an essential requirement prior to clinical trial participation, however some ‘vulnerable’ groups, such as people with cognitive impairments and those in medical emergency situations, may lack decisional capacity to consent. This raises ethical and practical challenges when designing and conducting clinical trials involving these populations, who are frequently excluded as a result. Despite recent advances in improving informed consent processes, there has been far less attention paid to the enrolment of adults lacking capacity.

Exclusion criteria are an important determinant of the external validity of clinical trial results. The exclusion of these populations, and consent-based recruitment biases which arise from the challenges of identifying and involving surrogate decision-makers, leads to trials which are not representative of the clinical population.

This article discusses the involvement of adults who lack decisional capacity to consent in clinical trials and presents the advances over the previous decade and the remaining ethical challenges for the inclusion of this under-represented population in research.

Informing Informed Consent for HIV Research
Research Article
Laura M. Campbell, Emily W. Paolillo, Robert Bryan, Jennifer Marquie-Beck, David J. Moore, Camille Nebeker, Raeanne C. Moore
Journal of Empirical Research on Human Research Ethics, 19 June 2020
Abstract
“Respect for Persons” is an ethical principle demonstrated through the informed consent process. Participants at a large HIV research center were surveyed to identify important aspects of the consent process. Persons with and without HIV (n = 103) completed a short pre/post questionnaire with both open-ended and forced choice response options. Qualitative analysis resulted in eleven themes about the most important consent elements which did not differ by HIV serostatus. Overall, participants rated the informed consent content and presentation by research staff as “extremely informative” and found the consent information to be “extremely consistent” with their study experience. Study results support the value of an interactive process and can be used to inform the design of a standardized, digital consent process.

Communication Training for Obtaining Informed Consent for Medical Research [BOOK CHAPTER]
N. Ananthakrishnan
Effective Medical Communication
Springer, 17 June 2020; pp 63-76
Abstract
Medical practice requires constant interaction between health care providers and those who seek care at these facilities. In addition, modern medicine also requires a strong focus on continued research for the benefit of mankind. It is estimated that the doubling time of medical knowledge in 1950 was 50 years; in 1980, 7 years; and in 2010, 3.5 years. In 2020, it is projected to be 0.2 years—just 73 days [1]. According to an estimate, students who join medicine in 2010 would experience three doublings before they complete the course, and those who join in 2020 would experience four doublings [1]. Medical research on either patients or other subjects/volunteers has, therefore, become an undeniable existential fact of medical practice.

An under-represented and underserved population in trials: methodological, structural, and systemic barriers to the inclusion of adults lacking capacity to consent
Commentary
Victoria Shepherd
BMC Trials, 29 May 2020; 21(445) 
Open Access
Abstract
Background
There is increasing international recognition that populations included in trials should adequately represent the population treated in clinical practice; however, adults who lack the capacity to provide informed consent are frequently excluded from trials. Addressing the under-representation of groups such as those with impaired capacity to consent is essential to develop effective interventions and provide these groups with the opportunity to benefit from evidence-based care. While the spotlight has been on ensuring only appropriate and justifiable exclusion criteria are used in trials, barriers to the inclusion of adults lacking capacity are multifactorial and complex, and addressing their under-representation will require more than merely widening eligibility criteria. This commentary draws on the literature exploring the inclusion of adults lacking the capacity to consent in research and a number of recent studies to describe the methodological, structural, and systemic factors that have been identified.
Main text
A number of potentially modifiable factors contributing to the under-representation of adults lacking the capacity to consent in trials have been identified. In addition to restrictive eligibility criteria, methodological issues include developing appropriate interventions and outcome measures for populations with impaired capacity. Structurally determined factors include the resource-intensive nature of these trials, the requirement for more appropriate research infrastructure, and a lack of interventions to inform and support proxy decision-makers. Systemic factors include the complexities of the legal frameworks, the challenges of ethical review processes, and paternalistic attitudes towards protecting adults with incapacity from the perceived harms of research.
Conclusions
Measures needed to address under-representation include greater scrutiny of exclusion criteria by those reviewing study proposals, providing education and training for personnel who design, conduct, and review research, ensuring greater consistency in the reviews undertaken by research ethics committees, and extending processes for advance planning to include prospectively appointing a proxy for research and documenting preferences about research participation. Negative societal and professional attitudes towards the inclusion of adults with impaired capacity in research should also be addressed, and the development of trials that are more person-centred should be encouraged. Further work to conceptualise under-representation in trials for such populations may also be helpful.

Cancer clinical trial consent forms: A readability analysis
Health Services Research and Quality Improvement
Mohana Roy, Lidia Schapira
Journal of Clinical Oncology, 25 May 2020; 38(15) supplement e19075
Abstract
Background: The National Cancer Institute (NCI) provides a template for cancer clinical trial consent forms and recommends a reading grade level of eighth grade or lower for such forms. This recommendation aligns with the goal of making clinical trials accessible to more patients. Methods: We surveyed clinical trial leaders at a large tertiary academic cancer center, to provide consent forms for active or recently closed, interventional cancer clinical trials (as of 2019). We requested forms that were preferably from multi-center trials and those perceived to have the highest accruals. We received 26 consent forms representing nine disease groups. Results: The average Flesh-Kincaid reading grade level was 11.2 (reflecting a 11th grade reading level), and no single form met the 8th grade reading level mark. The grade levels were assessed with three additional readability analyses (SMOG, FORCAST, and Raygor, see Table). The average Flesch reading ease was 50.7, rated as “fairly difficult”, with a scale of 0-100 (100 =“very easy” to read). The general HIPAA consent followed similar patterns, with a reading level of 10.9 and a reading ease of 49.2. There was an average of 18-20 words used per sentence. The reading levels and ease did not significantly vary with disease group or phase of trial. Conclusions: The overall readability level of cancer clinical trial forms, at our center, still require at least at least a 10th grade reading level. These forms may be difficult to understand for those with lower English proficiency and/or health literacy. We recommend a basic readability screen of such forms, and use of shorter sentences and simplified writing structure, to aid in comprehension.

The use of patient health information outside the circle of care: Consent preferences of patients from a large academic cancer centre
Care Delivery and Regulatory Policy
Fei Fei Liu, Sarah Tosoni, Indu S Voruganti, Rebecca Wong, Carl Virtanen, Donald Willison, Ann Heesters
Journal of Clinical Oncology, 25 May 2020; 38(15) supplement e14122
Abstract
Background: Massive volumes of patient health information (PHI) are required to realize the anticipated benefits of artificial intelligence in future clinical medicine. To maintain public trust in medical research however, consent policies must evolve to reflect contemporary patient preferences. Methods: From January-December 2019, patients attending clinics at a large academic cancer centre were invited to complete a 27-item iPad survey on consent preferences. Survey items focused on: (a) broad vs. specific consent; (b) opt-in vs. opt-out approaches for research contact; (c) comfort sharing with different recipients; (d) perceptions on commercialization; and (e) options to track information use and study results. Demographic questions addressed cancer type, treatment stage, age, gender, ethnicity, education level, and household income. Results: A total of 222 participants were included in the analysis (112 males, 108 females; 2 rather not say); 83% were comfortable sharing PHI with researchers at their own hospital. While 56% of patients preferred broad consent, 38% preferred to be contacted with study details and asked to consent every time (specific consent); 6% prefer not to share at all. Younger patients ( < 49 years) most often chose specific consent (50%); significantly more than those 75+ years (24%; p < .05). Younger patients ( < 49 years) were also significantly more uncomfortable than older patients (50+ years) sharing even within their own hospital (13% uncomfortable vs. 1% uncomfortable; p < .05). A significant majority of patients (63%, p = .0001) preferred to be asked for permission before being entered into a contact pool vs. automatic entry with opportunity to opt-out. The majority of patients were uncomfortable sharing PHI with commercial enterprises (51% uncomfortable, 27% comfortable, 22% neutral). A significant majority expressed the desire to track who is using their PHI (61%, p < .0001), and be notified regarding study results (70%, p < .0001). Conclusions: While most patients were willing to share their PHI with researchers at their own hospital, many preferred a transparent and reciprocal consent process. These data also suggest a generational shift, wherein younger patients preferred more informed consent options. Modernizing consent policies to reflect increased patient interest in the exercise of their autonomy is crucial in fostering sustained public engagement in medical research.

Informed consent in phase I clinical trials: Implications for trends in design
Care Delivery and Regulatory Policy
Paul Henry Frankel, Susan G. Groshen
Journal of Clinical Oncology, 25 May 2020; 38(15) supplement e14077
Abstract
Background: Informed Consent (IC) is a critical aspect of human subjects protection. Institutional Review Boards are tasked with insuring proper IC as one aspect of protecting participants in clinical trials. Phase I trials in oncology present special issues with IC, as often neither the risks nor the benefits are well-known. This has resulted in carefully worded IC templates for Phase I studies based on the traditional use of dose-finding designs that are geared towards finding the “Maximum Tolerated Dose (MTD)”. As the definition of this term varies by study, the implication for patient risk and informed consent are rarely discussed. Methods: We reviewed Phase I designs to present options for improving the informed consent process for Phase I oncology trials. Results: Phase I studies have seen an increase in designs based on work from the early 1990s seeking a dose that results in a targeted percent of patients experiencing a “Dose Limiting Toxicity (DLT)” to define the MTD. The most common definition of a DLT is a treatment-related toxicity that results in a particularly concerning severe toxicity (grade 3 or higher) in the first cycle of therapy and the most common rate targeted (in designs that define toxicity as a goal) is 25%. In that setting, while lower doses may have a lower likelihood of DLT, higher doses or the expansion cohort are likely to have a 25% chance of DLT if the target is pursued. This information is rarely quantitatively communicated in the informed consent. Conclusions: IRBs and investigators should consider communicating through informed consent the quantitative summary of goals of the study and related risk. For example, transparency suggests conveying when the goal (target) of the study is to find the dose where there is a one in four chance of experiencing a severe adverse event in the first cycle.