Category: Spotlight

Spotlight

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This month we have chosen to highlight the posting of informed consent forms (ICFs) on clinicaltrials.gov by industry funded trials. In the American Association of Pharmaceutical Scientists Journal article ‘Principal Features of Industry-Funded Trials that Posted Informed Consent Forms on ClinicalTrials.gov: a Cross-Sectional Analysis’ Dal-Ré and Mahillo-Fernández advocate for a new regulatory standard requiring the posting of ICFs. The authors found that of 116,281 industry funded trials only 741, or 0.6%, posted their ICFs on clinicaltrials.gov. We note from other ongoing work undertaken by the Center for Informed Consent Integrity that there are currently over 9,000 ICFs posted, making the 741 available from industry funded trials even more striking.

The article finds that when industry sponsors do make their ICFs available, they are highly compliant with transparency standards, seemingly having found a resolution to the general objection from commercial organizations that the posting of ICFs would reveal trade secrets and/or ongoing research programs. These findings raise questions about how to increase the availability of ICFs and enhance shared learning across the field of informed consent.

Principal Features of Industry-Funded Trials that Posted Informed Consent Forms on ClinicalTrials.gov: a Cross-Sectional Analysis
Rafael Dal-Ré, Ignacio Mahillo-Fernández
American Association of Pharmaceutical Scientists Journal, 18 June 2024; 26(4)
Abstract
We aim to characterize industry-funded trials that have posted the informed consent forms (ICFs), and to assess whether the role played by industry as ‘sponsor’ or ‘collaborator’ could impact several relevant variables. A cross-sectional study was conducted on ClinicalTrials.gov on all industry-funded trials registered on or before 25 February 2023. We registered types of intervention, current recruitment status, design, enrollment, and countries involved. For trials with special interest to potential participants and investigators and/or clinicians an analysis of the role played by industry as ‘sponsor’ or ‘collaborator’ was performed. Of 116,281 industry-funded trials registered, 741 (0.6%) had posted ICFs. Most of these trials were categorized as ‘completed’ (n = 408) or ‘terminated’ (n = 107). The review of a sample of 359 trials showed that most were on drugs and/or biologics (59%), were randomized (51%), conducted exclusively in the USA (72%), and had posted results (79%), protocols (92%), and statistical analysis plans (SAPs) (89%). Trials in which industry participated as ‘collaborator’ were significantly more likely to post ICFs when trials were in the ‘active, not recruiting’ phase (OR 4.70, 99.71% CI 1.59-13.9, p < 0.001) than industry-sponsored trials. This was also the case when assessing drugs/biologics (OR 2.64, 99.71% CI 1.25-5.58, p < 0.001). Conversely, companies acting as ‘sponsors’ were significantly more likely to post ICFs with trials assessing devices, radiation interventions and/or diagnostic tests (OR 0.37, 99.71% CI 0.17-0.79, p < 0.001) than when participating as ‘collaborators’. While industry-funded trials rarely post ICFs, when they do, they are highly compliant with transparency requirements. Regulations and ethics codes should consider requiring posting of protocols, SAPs, and ICFs for all clinical trials, regardless the type of sponsor.

Spotlight Section

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This month we would like to spotlight two articles focused on the applications of artificial intelligence technologies in healthcare. In an article in Machine Learning and Knowledge Extraction – Evaluation of AI ChatBots for the Creation of Patient-Informed Consent Sheets – Raimann et al. assessed the ability of large language models (LLMs) to generate information sheets for six basic anesthesiologic procedures.The authors found that that the three LLMs tested fulfilled less than 50% of the predetermined requirements for a satisfactory and compliant information sheet. They also found that the descriptions of key elements such as risks and documentation regarding consultation varied. The authors assess that LLMs have “clear limitations” in generating patient information sheets.

Park addresses the patient perspective on AI use in healthcare provision in the Digital Health article – Patient perspectives on informed consent for medical AI: A web-based experiment. Through this work Park adds a new voice to the debate about whether, when using LLMs as a decision aid, healthcare providers ought to disclose this to the patients. It was found that patients trust second opinions from other physicians more than an AI diagnosis, but as the risk level increased for procedures, as did the importance of AI generated information. This study found the disclosure of AI use in diagnosis to be necessary from a patient perspective.

The Center for Informed Consent Integrity is exploring use of ChatGPT 4.0 to analyze the informed consent landscape, specifically how the 60+ editions of this digest might function as a specific content base for inquiry. We have encountered some limitations given our purpose, albeit different than those found by the authors below. We will continue to explore generative AI to strengthen our work and keep our readers updated.

Evaluation of AI ChatBots for the Creation of Patient-Informed Consent Sheets
Florian Jürgen Raimann, Vanessa Neef, Marie Charlotte Hennighausen, Kai Zacharowski, Armin Niklas Flinspach
Machine Learning and Knowledge Extraction, 24 May 2024
Abstract
Introduction
Large language models (LLMs), such as ChatGPT, are a topic of major public interest, and their potential benefits and threats are a subject of discussion. The potential contribution of these models to health care is widely discussed. However, few studies to date have examined LLMs. For example, the potential use of LLMs in (individualized) informed consent remains unclear.
Methods
We analyzed the performance of the LLMs ChatGPT 3.5, ChatGPT 4.0, and Gemini with regard to their ability to create an information sheet for six basic anesthesiologic procedures in response to corresponding questions. We performed multiple attempts to create forms for anesthesia and analyzed the results checklists based on existing standard sheets.
Results
None of the LLMs tested were able to create a legally compliant information sheet for any basic anesthesiologic procedure. Overall, fewer than one-third of the risks, procedural descriptions, and preparations listed were covered by the LLMs.
Conclusions
There are clear limitations of current LLMs in terms of practical application. Advantages in the generation of patient-adapted risk stratification within individual informed consent forms are not available at the moment, although the potential for further development is difficult to predict. 

Patient perspectives on informed consent for medical AI: A web-based experiment
Hai Jin Park
Digital Health, 30 April 2024
Abstract
Objective
Despite the increasing use of AI applications as a clinical decision support tool in healthcare, patients are often unaware of their use in the physician’s decision-making process. This study aims to determine whether doctors should disclose the use of AI tools in diagnosis and what kind of information should be provided.
Methods
A survey experiment with 1000 respondents in South Korea was conducted to estimate the patients’ perceived importance of information regarding the use of an AI tool in diagnosis in deciding whether to receive the treatment.
Results
The study found that the use of an AI tool increases the perceived importance of information related to its use, compared with when a physician consults with a human radiologist. Information regarding the AI tool when AI is used was perceived by participants either as more important than or similar to the regularly disclosed information regarding short-term effects when AI is not used. Further analysis revealed that gender, age, and income have a statistically significant effect on the perceived importance of every piece of AI information.
Conclusions
This study supports the disclosure of AI use in diagnosis during the informed consent process. However, the disclosure should be tailored to the individual patient’s needs, as patient preferences for information regarding AI use vary across gender, age and income levels. It is recommended that ethical guidelines be developed for informed consent when using AI in diagnoses that go beyond mere legal requirements.

 

Spotlight Articles

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This month we Spotlight the article by Landi et al. in Frontiers in Medicine, The creation of an adaptable informed consent form for research purposes to overcome national and institutional bottlenecks in ethics review: experience from rare disease registries. This ambitious article addresses variability and inconsistency in the consent process in the EU context and suggests a method for overcoming these challenges. The authors developed a template that allowed participants options to consent to participation independently of consenting to the reuse of their data, an area which is the target of much current thinking. We note discussion of the creation of an adaptable assent template, the pediatric material is being finalized to collect minors’ assent, and that “ICF machine-readability is also progressing to enhance data discovery and facilitate its access and reuse conditions.”

The creation of an adaptable informed consent form for research purposes to overcome national and institutional bottlenecks in ethics review: experience from rare disease registries
Original Research
Annalisa Landi, Yanis Mimouni, Viviana Giannuzzi, Franz Schaefer, Annagrazia Altavilla, Spencer Gibson, Daria Julkowska
Frontiers in Medicine, 27 March 2024
Abstract
Background
The lack of harmonization of evaluation criteria by Ethics Committees in the European Union (EU) has led to inconsistent ethics reviews received by research sites participating in multicenter non-interventional studies. The European General Data Protection Regulation (GDPR) appears to be implemented at national level with a substantial degree of variance in interpretation. The European Reference Networks (ERNs) were struggling in setting an Informed Consent Form (ICF) for registries, allowing reuse of data for research purposes. The aim of this work is to develop an adaptable ICF for research purposes to be used in ERN registries.
Methods
To work on this challenge, a team was established within the European Joint Programme on Rare Diseases (EJP RD) to develop a patients’ registry ICF template allowing easy adaptation to ERNs, country, and site-level specificities. ERN and patients’ representatives validated the choice of developing a GDPR-compliant template for research purposes. The feedback received from 34 Ethics Committees on the Clinical Patient Management System ICF, including the submission of patients’ data to the ERN registries and the EU consent regulatory framework were analysed along with existing ontologies for data access and reuse. An adaptable ICF was developed following iterative cycles of consultation and review by clinicians, research experts, ethics and regulatory advisors, and patients’ representatives. The development of pediatric material for minor participants was also undertaken.
Results & Conclusions
Research oriented ICF templates for adults and for parents/legal representatives of patients were released in 26 national languages. This adaptable ICF aims to foster, according to patients’ preferences, the reuse of registries data for research purposes in compliance with the applicable laws and standards. Pediatric material is being finalized to collect minors’ assent. ICF machine-readability is also progressing to enhance data discovery and facilitate its access and reuse conditions.

Spotlight Articles

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We recognize a growing literature which argues [in whole or in part] that norms requiring the individual, prior, free, express and informed consent of persons to be involved in research must accommodate notions which integrate terms such as ‘community-driven’, ‘decolonized’, or ‘culturally-appropriate’ and which insist that consent processes “prioritize local/indigenous values and protocols.” As an editorial policy, we have decided to group such literature together in this section of the digest.

More broadly, we recognize that this literature raises critically important issues around consent integrity. Our Center for Informed Consent Integrity is actively developing a position on this matter, mindful of core guidance in research involving human participants overall, and selected instruments such as the Universal Declaration on Bioethics and Human Rights [2005] which notes:

Article 12.  Respect for cultural diversity and pluralism

The importance of cultural diversity and pluralism should be given due regard. However, such considerations are not to be invoked to infringe upon human dignity, human rights and fundamental freedoms, nor upon the principles set out in this Declaration, nor to limit their scope.

We will keep readers advised of our progress. If you have an interest in participating in our working group, please contact Paige Fitzsimmons [paige.fitzsimmons@ge2p2global.org].

Balancing Ethics and Culture: A Scoping Review of Ethico-Cultural and Implementation Challenges of the Individual-Based Consent Model in African Research
Richard Appiah, Giuseppe Raviola, Benedict Weobong
Journal Of Empirical Research On Human Research Ethics, 18 March 2024
Abstract
Objective
This review explores the ethico-cultural and implementation challenges associated with the individual-based informed consent (IC) model in the relatively collectivistic African context and examines suggested approaches to manage them.
Methods
We searched four databases for peer-reviewed studies published in English between 2000 to 2023 that examined the ethico-cultural and implementation challenges associated with the IC model in Africa.
Results
Findings suggest that the individual-based IC model largely misaligns with certain African social values and ethos and subverts the authority and functions of community gatekeepers. Three recommendations were proffered to manage these challenges, that researchers should: adopt a multi-step approach to IC, conduct a rapid ethical assessment, and generate an African-centered IC model.
Conclusions
A pluriversal, context-specific, multi-step IC model that critically harmonizes the cultural values of the local population and the general principles of IC can minimize ethics dumping, safeguard the integrity of the research process, and promote respectful engagement.

Culturally Competent Respect For The Autonomy Of Muslim Patients: Fostering Patient Agency By Respecting Justice
Kriszta Sajber, Sarah Khaleefah
Theoretical Medicine and Bioethics, 7 February 2024
Abstract
Although Western biomedical ethics emphasizes respect for autonomy, the medical decision-making of Muslim patients interacting with Western healthcare systems is more likely to be motivated by relational ethical and religious commitments that reflect the ideals of equity, reciprocity, and justice. Based on an in-depth cross-cultural comparison of Islamic and Western systems of biomedical ethics and an assessment of conceptual alignments and differences, we argue that, when working with Muslim patients, an ethics of respect extends to facilitating decision-making grounded in the patient’s justice-related customs, beliefs, and obligations. We offer an overview of the philosophical contestations of autonomy-enhancing practices from the Islamic tradition of biomedical ethics, and examples that demonstrate a recommended shift of emphasis from an autonomy-centered to a justice-focused approach to culturally competent agency-promotion.

Spotlight Articles

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Recognizing the emergence of large language models (LLMs) and generative AI, our spotlight section this month focuses on articles which appeared the Journal of Medical Ethics, published online on January 23rd 2024. The articles address the use of LLMs and generative AI in informed consent procedures and, more broadly, the  use of this technology within the medical ethics space.

In the editorial by Zohny et al, Generative AI and medical ethics: the state of play, the authors provide an overview of how LLMs are being used in medical ethics currently, and note that the technology lacks the maturity for nuanced ethical decision making at this time.

Allen et al. address the potential for LLMs to be used to facilitate surgical consent transactions with patients in Consent-GPT: is it ethical to delegate procedural consent to conversational AI? The authors raise several concerns with this practice, including the risk of misinformation, the absence of trust that one might have in the doctor-patient relationship, the potential for ‘click-through’ consent rather than fulsome consent, and the lack of clarity surrounding who has responsibility for an LLM informed consent transaction.

In Assessing the performance of ChatGPT in bioethics: a large language model’s moral compass in medicine, Chen et al. assess that LLMs have the potential to address certain aspects of medical ethics that required social intelligence but struggled in nuanced areas such as informed consent transactions.

Finally, Balas et al. found in Exploring the potential utility of AI large language models for medical ethics: an expert panel evaluation of GPT- 4 that when faced with ethical decision making, LLMs were able to articulate the principled issues at hand but without much understanding or depth to what each issue might translate to in terms of patient experience LLMs tested were also unable to integrate ethical and legal concepts in a satisfactory manner. The authors believe that at the moment AI may be used to compliment, but not replace, healthcare practitioner involvement in informed consent transactions.

Generative AI and medical ethics: the state of play
Editorial
Hazem Zohny, Sebastian Porsdam Mann, Brian D Earp, John McMillan
Journal of Medical Ethics, 23 January 2024
Excerpt
Since their public launch, a little over a year ago, large language models (LLMs) have inspired a flurry of analysis about what their implications might be for medical ethics, and for society more broadly. Much of the recent debate has moved beyond categorical evaluations of the permissibility or impermissibility of LLM use in different general contexts (eg, at work or school), to more fine-grained discussions of the criteria that should govern their appropriate use in specific domains or towards certain ends. With each passing week, it seems more and more inevitable that LLMs will be a pervasive feature of many, if not most, of our lives. It would not be possible—and would not be desirable—to prohibit them across the board. We need to learn how to live with LLMs; to identify and mitigate the risks they pose to us, to our fellow creatures, and the environment; and to harness and guide their powers to better ends. This will require thoughtful regulation, sustained cooperation across nations, cultures and fields of inquiry; and all of this must be grounded in good ethics…

Consent-GPT: is it ethical to delegate procedural consent to conversational AI?
Current Controversy
Jemima Winifred Allen, Brian D Earp, Julian Koplin, Dominic Wilkinson
Journal of Medical Ethics, 23 January 2024
Abstract
    Obtaining informed consent from patients prior to a medical or surgical procedure is a fundamental part of safe and ethical clinical practice. Currently, it is routine for a significant part of the consent process to be delegated to members of the clinical team not performing the procedure (eg, junior doctors). However, it is common for consent-taking delegates to lack sufficient time and clinical knowledge to adequately promote patient autonomy and informed decision-making. Such problems might be addressed in a number of ways. One possible solution to this clinical dilemma is through the use of conversational artificial intelligence using large language models (LLMs). There is considerable interest in the potential benefits of such models in medicine. For delegated procedural consent, LLM could improve patients’ access to the relevant procedural information and therefore enhance informed decision-making.
In this paper, we first outline a hypothetical example of delegation of consent to LLMs prior to surgery. We then discuss existing clinical guidelines for consent delegation and some of the ways in which current practice may fail to meet the ethical purposes of informed consent. We outline and discuss the ethical implications of delegating consent to LLMs in medicine concluding that at least in certain clinical situations, the benefits of LLMs potentially far outweigh those of current practices.

Assessing the performance of ChatGPT in bioethics: a large language model’s moral compass in medicine
Original research
Jamie Chen, Angelo Cadiente, Lora J Kasselman, Bryan Pilkington
Journal of Medical Ethics, 23 January 2024
Abstract
Chat Generative Pre-Trained Transformer (ChatGPT) has been a growing point of interest in medical education yet has not been assessed in the field of bioethics. This study evaluated the accuracy of ChatGPT-3.5 (April 2023 version) in answering text-based, multiple choice bioethics questions at the level of US third-year and fourth-year medical students. A total of 114 bioethical questions were identified from the widely utilised question banks UWorld and AMBOSS. Accuracy, bioethical categories, difficulty levels, specialty data, error analysis and character count were analysed. We found that ChatGPT had an accuracy of 59.6%, with greater accuracy in topics surrounding death and patient–physician relationships and performed poorly on questions pertaining to informed consent. Of all the specialties, it performed best in paediatrics. Yet, certain specialties and bioethical categories were under-represented. Among the errors made, it tended towards content errors and application errors. There were no significant associations between character count and accuracy. Nevertheless, this investigation contributes to the ongoing dialogue on artificial intelligence’s (AI) role in healthcare and medical education, advocating for further research to fully understand AI systems’ capabilities and constraints in the nuanced field of medical bioethics.

Exploring the potential utility of AI large language models for medical ethics: an expert panel evaluation of GPT-4
Original Research
Michael Balas, Jordan Joseph Wadden, Philip C Hébert, Eric Mathison, Marika D Warren, Victoria Seavilleklein, Daniel Wyzynski, Alison Callahan, Sean A Crawford, Parnian Arjmand, Edsel B Ing
Journal of Medical Ethics, 23 January 2024
Abstract
    Integrating large language models (LLMs) like GPT-4 into medical ethics is a novel concept, and understanding the effectiveness of these models in aiding ethicists with decision-making can have significant implications for the healthcare sector. Thus, the objective of this study was to evaluate the performance of GPT-4 in responding to complex medical ethical vignettes and to gauge its utility and limitations for aiding medical ethicists. Using a mixed-methods, cross-sectional survey approach, a panel of six ethicists assessed LLM-generated responses to eight ethical vignettes.
The main outcomes measured were relevance, reasoning, depth, technical and non-technical clarity, as well as acceptability of GPT-4’s responses. The readability of the responses was also assessed. Of the six metrics evaluating the effectiveness of GPT-4’s responses, the overall mean score was 4.1/5. GPT-4 was rated highest in providing technical (4.7/5) and non-technical clarity (4.4/5), whereas the lowest rated metrics were depth (3.8/5) and acceptability (3.8/5). There was poor-to-moderate inter-rater reliability characterised by an intraclass coefficient of 0.54 (95% CI: 0.30 to 0.71). Based on panellist feedback, GPT-4 was able to identify and articulate key ethical issues but struggled to appreciate the nuanced aspects of ethical dilemmas and misapplied certain moral principles.
This study reveals limitations in the ability of GPT-4 to appreciate the depth and nuanced acceptability of real-world ethical dilemmas, particularly those that require a thorough understanding of relational complexities and context-specific values. Ongoing evaluation of LLM capabilities within medical ethics remains paramount, and further refinement is needed before it can be used effectively in clinical settings.

Spotlight Articles

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This month our spotlight section focuses on the practical development of approaches to obtain assent from persons who may not be able to provide full informed consent. Assent is of particular interest to the GE2P2 Global Foundation and we welcome any thoughts or engagement our readers may want to share.

In the Psychology in the Schools research article Review of participatory research assent procedures in school psychology, Flowers et al. point out that ‘[t]ransparency in research is vital for advancing science and safeguarding research participants’ and provide the following recommendations for practitioners:

  • Given the findings that only a small percentage of reviewed articles provided a detailed account of how assent was obtained from children and adolescent participants, it is crucial for practitioners in school psychology research to prioritize and transparently document their assent procedures.
  • While the current review did not identify novel methods for obtaining assent in school psychology research, practitioners should consider looking to related fields for potentially innovative approaches. Engaging participants in a way that enhances their understanding and buy‐in can lead to more accurate and valid research outcomes.
  • Researchers and practitioners in school psychology should advocate for clear reporting standards regarding assent procedures in publications. Providing detailed information about the assent process should be seen as essential to ethical research, and authors and journal editors should consider the value of including this information in their manuscripts.

In Maureen Dykinga’s University of Arizona PhD Dissertation Promoting Health Literacy by Operationalizing a Developmental Approach to Assent, the author finds that in the University of Arizona context, there is a ‘need for operationalized resources that already contain simplified language for PIs to use when assenting youth’. Dykinga notes this research is important for ‘deepening our understanding of the effect age has on interventions and the course of diseases [as this] is dependent upon youth-specific data’.

Review of participatory research assent procedures in school psychology
Research Article
Jaime Flowers, Daniel McCleary, Jillian Dawes, Hunter Marzolf
Psychology in the Schools, 5 December 2023
Abstract
In the realm of psychology and related fields, like school psychology, obtaining informed consent from clients or participants who are 18 years old or older is mandatory for researchers. However, if the individuals are below 18 years old or under a conservatorship, their assent is crucial even if their parent or legal guardian has provided formal consent. Despite the widespread recognition of the importance of assent during research, there is a lack of research and guidelines on how to obtain it effectively. To bridge this gap, we conducted a review and created a summary of research published in school psychology journals on gaining assent during research studies. The articles were categorized based on the experimental design, population, and level of assent described. Our findings offer a comprehensive overview of the current state of research on gaining assent in school psychology, which will enhance transparency in research methods.

Promoting Health Literacy by Operationalizing a Developmental Approach to Assent
PhD Dissertation
Maureen Dykinga
PhD Thesis, 2023 [University of Arizona]
Open Access
Abstract
Background
Since 1991, The Common Rule has provided regulation to protect humans participating in biomedical or social research. Despite clear protocols to obtain informed consent from adults, there is limited information on how to incorporate developmental factors such as simplified language, formative assessment, and feedback into youth assent practices. Adolescence, an important period for developing behaviors that impact health throughout the lifespan, is also a time when developmental capabilities vary greatly among peers of the same chronological age. Meaningfully engaging youth in research begins with an assent that integrates developmental factors and promotes the health literacy of youth. Operationalizing this approach narrows the gap between regulation and research practices.
Methods
To quantify the language complexity of two assent templates, 3 trained speech-language pathologists used Language Sample Analysis; the results were compared. To assess the usefulness of incorporating development into assent, a developmental approach to assent was designed. This approach was implemented with a randomized sample of 50 youth participating in the Children And Teens Study (CATS). A data capture system was utilized to present simplified assent language in segments and ask 6 questions assessing comprehension. For individuals with incorrect answers, feedback was provided, and the same question was presented a second time. To incorporate youth priorities, values, and strengths into assent resources, demographics, educational experiences, exposure to racism, and resiliency data were analyzed. To evaluate the feasibility of shifting institutional assent practices, semi-structured interviews were conducted, assessing the importance of assent, understanding of a developmental approach, its acceptability, the practicality of requiring it, and the resources needed for Principal Investigators (PIs), to be successful. To design a toolkit of operational resources, the knowledge from implementing a developmental approach, analyzing youth data, and conducting the feasibility study was applied.
Results
The simplified assent conveyed the same number of key study details as the more complex assent. 100% of the 6 questions were answered accurately by participants. The cross-section of the youth represented a diverse mix of demographics with 72% reporting comorbidities that impact language, learning, mental, and chronic health. Ninety-eight percent indicated an awareness of racism while 16% had encountered it directly. Youth valued education/knowledge and prioritized flexibility, agency, and autonomy. They demonstrated strengths such as cooperation, connection, and belonging. PIs indicated that assent was important and incorporating a developmental approach was acceptable. They did not believe it would be practical to require this approach. Key barriers were identified as securing buy-in from researchers, addressing time constraints, and gaining institutional support. Resources that strengthen capacity, provide examples, and allow for flexibility, were identified as a need by researchers. A toolkit of resources that reflected youth awareness, priorities, values, and strengths while meeting researcher requests was developed and made available in the resources section of the University of Arizona (UArizona) Institutional Review Board (IRB) website.
Conclusion
The results suggest that integrating a developmental approach was useful in communicating key study elements and reinforced the necessity for inclusive assent practices that align with youth awareness. Incorporating developmental factors into assent empowers youth to exercise health literacy. Providing operational assent resources that reflect the values of diverse youth communities and strengthen the capacity of PIs is the first of many strategies to meaningfully engage youth in research.

Spotlight Article

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This month we are spotlighting The Lived Experience of Pediatric Gene Therapy – A Scoping Review by Kimberly et al. In this Human Gene Therapy article the authors assess empirical research examining the lived experience of both patients and caregivers participating in pediatric gene therapy trials. Their scoping review underscores a serious gap in the literature leading to an examination of narrative accounts from trial participants and their families, and areas where further research in necessary. The authors note that:

[p. 4]
“…When making a decision about whether to enroll a child in a GT clinical trial, caregivers must weigh factors such as: the inability for most treatments to be repeated or re-dosed; uncertainty around the durability, efficacy, and safety of an experimental treatment; risk of a child’s disease progressing if they wait for an approved treatment or more safety data; and efficacy of existing approved alternative treatments… The confluence of these factors within a high-stakes decision-making framework creates a unique ethical context for pediatric rare disease patients and their parents and caregivers. The progressive nature of many of these diseases also adds a time constraint to participation…

[p. 16]
The field of pediatric GT research… has an important and timely opportunity to better understand how patients and their parents/caregivers choose whether or not to consider GT, and their lived experience of participating in clinical trials. Pediatric patients’ own perspectives are almost completely absent from the literature, marking an important area for future research efforts. Such insights from further research will inform more patient- and family-centered clinical trial design and can help to ensure that clinical trial design and implementation reflect patients’ and families’ values, their priorities, and their goals for care. This scoping review lays a foundation for future research in this space.”

The Lived Experience of Pediatric Gene Therapy – A Scoping Review
Laura Kimberly, Cara Hunt, Katherine Beaverson, Emma James, Alison Bateman-House, Richard McGowan, Jennifer DeSante-Bertkau
Human Gene Therapy, 15 November 2023
Abstract
Little is known about patients’ and families’ lived experience of participating in pediatric gene therapy (GT) clinical trials. Currently, pediatric GT research targets a broad range of indications––including rare and ultra-rare diseases––which vary in severity and in the availability of alternative therapies. Pediatric GT differs meaningfully from adult GT because the decision to participate involves a dyad of both the child and parent or caregiver/s. It is critical to understand patients’ and caregivers’ perceptions and experiences of the social, emotional, physical, and logistical burdens or benefits of participating in such trials, and how they weigh and prioritize these factors when deciding whether to participate. We conducted a scoping review of the current literature in this subject area with objectives to a) provide an overview of existing literature, b) identify gaps and areas for further research, and c) better understand the lived impact of pediatric GT research on patients and their parents/caregivers. , Four themes emerged, including 1) weighing risks and benefits 2) timing of GT trial participation 3) value of clear communication, and 4) potential impact on quality of life. Notably, our sample surfaced articles about how patients/parents/caregivers were thinking about GT – their understanding of its safety, efficacy, and risks – rather than accounts of their experiences, which was our initial intention. Nevertheless, our findings offer useful insights to improve the informed consent process and promote a more patient- and family-centered approach. Moreover, our findings can contribute to patient advocacy organizations’ efforts to develop educational materials tailored to patients’ and families’ expressed informational needs and perspectives, and can inform more patient- and family-centered policies from GT clinical trial sponsors.

Spotlight Articles

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Generative AI – and LLMs [Large Language Models] which drive it – are receiving extensive (and appropriate) attention in the media, in regulatory contexts and in the academic literature. We feature here two articles which explore some of the intersections between generative AI and consent. The first, by Decker et al., explores how LLMs might be employed to potentially enhance ICF readability, improve articulation of risks, and “ease documentation burden for physicians.”  The second, by Litt et al., also explores improvements in readability through aggregating ICFs posted with oncology clinical trials registered on clinicaltrials.gov and then applying a generative AI tool generate more useful consent content. We anticipate a good deal more activity exploring how generative AI can contribute to consent content, effectiveness and integrity.

Large Language Model−Based Chatbot vs Surgeon-Generated Informed Consent Documentation for Common Procedures
Original Investigation Surgery
Hannah Decker, Karen Trang, Joel Ramirez, Alexis Colley, Logan Pierce, Melissa Coleman, Tasce Bongiovanni, Genevieve B. Melton, Elizabeth Wick
JAMA Network Open, 9 October 2023; 6(10)
Abstract
Importance
Informed consent is a critical component of patient care before invasive procedures, yet it is frequently inadequate. Electronic consent forms have the potential to facilitate patient comprehension if they provide information that is readable, accurate, and complete; it is not known if large language model (LLM)-based chatbots may improve informed consent documentation by generating accurate and complete information that is easily understood by patients.
Objective
To compare the readability, accuracy, and completeness of LLM-based chatbot- vs surgeon-generated information on the risks, benefits, and alternatives (RBAs) of common surgical procedures.
Design, Setting, and Participants
This cross-sectional study compared randomly selected surgeon-generated RBAs used in signed electronic consent forms at an academic referral center in San Francisco with LLM-based chatbot-generated (ChatGPT-3.5, OpenAI) RBAs for 6 surgical procedures (colectomy, coronary artery bypass graft, laparoscopic cholecystectomy, inguinal hernia repair, knee arthroplasty, and spinal fusion).
Main Outcomes and Measures
Readability was measured using previously validated scales (Flesh-Kincaid grade level, Gunning Fog index, the Simple Measure of Gobbledygook, and the Coleman-Liau index). Scores range from 0 to greater than 20 to indicate the years of education required to understand a text. Accuracy and completeness were assessed using a rubric developed with recommendations from LeapFrog, the Joint Commission, and the American College of Surgeons. Both composite and RBA subgroup scores were compared.
Results
The total sample consisted of 36 RBAs, with 1 RBA generated by the LLM-based chatbot and 5 RBAs generated by a surgeon for each of the 6 surgical procedures. The mean (SD) readability score for the LLM-based chatbot RBAs was 12.9 (2.0) vs 15.7 (4.0) for surgeon-generated RBAs (P = .10). The mean (SD) composite completeness and accuracy score was lower for surgeons’ RBAs at 1.6 (0.5) than for LLM-based chatbot RBAs at 2.2 (0.4) (P < .001). The LLM-based chatbot scores were higher than the surgeon-generated scores for descriptions of the benefits of surgery (2.3 [0.7] vs 1.4 [0.7]; P < .001) and alternatives to surgery (2.7 [0.5] vs 1.4 [0.7]; P < .001). There was no significant difference in chatbot vs surgeon RBA scores for risks of surgery (1.7 [0.5] vs 1.7 [0.4]; P = .38).
Conclusions and Relevance
The findings of this cross-sectional study suggest that despite not being perfect, LLM-based chatbots have the potential to enhance informed consent documentation. If an LLM were embedded in electronic health records in a manner compliant with the Health Insurance Portability and Accountability Act, it could be used to provide personalized risk information while easing documentation burden for physicians.

Improving clinical trial consent form readability through artificial intelligence
Conference Presentation – ASCO Quality Care Symposium 2023
Henry Kazunaru Litt, Emma Greenstreet Akman, Dame Idossa, Narjust Florez, Ana I. Velazquez Manana
JCO Oncology Practice – Health Care Access, Equity, and Disparities, 26 October 2023; 18(11)suppl
Abstract
Background
High literacy levels are needed to understand oncology clinical trial (CT) informed consent forms (ICF), which represents a barrier to enrollment of older adults and diverse populations. ChatGPT-4 is an artificial intelligence chatbot that responds to user prompts and can summarize large amounts of text. We tested whether ChatGPT-4 could simplify CT information from ICFs.
Methods
On May 22, 2023, we searched clinicaltrials.gov for interventional, therapeutic, NIH-funded, CTs involving adults with the 14 most prevalent cancer types. Only CTs with available study protocols that were currently recruiting, “enrolling by invitation”, and “active not recruiting” were included. Trials that were diagnostic, preventative, or supportive were excluded. Publicly available ICFs from the resulting CTs were downloaded and analyzed. Using the ChatGPT-4 plugin askyourpdf.com, we asked ChatGPT-4 to review each ICF and answer 8 questions recommended by the NCCN for patients considering a CT in a 6th grade literacy level. Our prompt included the following 8 questions: “1) What are the treatments used in the clinical trial? 2) Has the treatment been used for other types of cancer? 3) What are the risks and benefits of this treatment? 4) What side effects should I expect and how will they be managed? 5) How long will I be in the clinical trial? 6) Will I be able to get other treatment if this doesn’t work? 7) How will you know if the treatment is working? 8) Will the clinical trial cost me anything?” Reading level (readability) was assessed for both the ICFs and ChatGPT-4’s question responses using the validated Flesch-Kincaid (FK), Gunning Fog (GF), and SMOG indices using the online Readable App. Data was summarized with descriptive statistics and t-test was used to compare text reading levels between ICFs and ChatGPT-4’s answers.
Results
Our search yielded 83 therapeutic oncology CTs, of which 70 had publicly available ICFs. ChatGPT-4 successfully analyzed 66 of the 70 ICFs (94.3%). The mean text reading levels of its answers were 6.2 (95% CI: 5.9-6.5), 8.6 (95% CI: 8.2-8.9), and 9.2 (95% CI: 8.9-9.4) based on FK, GF, and SMOG indices, respectively. Of 70 ICFs, 54 (77.1%) contained text that could be evaluated for readability analysis and were included in the analysis. The mean text reading levels was 7.9 (95% CI: 7.7-8.1), 9.3 (95% CI: 9.1-9.6), and 10.5 (95% CI: 10.2-10.8) based on FK, GF, and SMOG indices, respectively. ChatGPT-4’s text responses had a significantly lower reading level compared to ICFs text for all three readability indices (FK: p<0.01, GF: p=0.02, SMOG: p<0.01).
Conclusions
ChatGPT-4 presented key information from oncology CT ICFs at a 6th to 9th grade reading level, which was significantly lower than the original ICFs. While further studies are needed to assess ChatGPT-4’s accuracy, this study shows its potential as tool for improving patients’ understanding of oncology CTs.

Spotlight Articles

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In the October spotlight section we have chosen to highlight an article which was included in the March 2023 edition of the digest, and has since been debated widely in the literature. The JME article by van der PiJl et al., The ethics of consent during labour and birth: episiotomies, focuses on consent in labour. The authors argue that current practice for consenting in labour and birth must be improved upon, and suggest ways a higher standard of consent in this space ought to be achieved. Below we present the original article which sparked the debate, followed by a selection of responses. The final article is a response from the authors of the original article.

The ethics of consent during labour and birth: episiotomies
Marit van der Pijl, Corine Verhoeven, Martine Hollander, Ank de Jonge, Elselijn Kingma
Journal of Medical Ethics, 30 January 2023
Abstract
Unconsented episiotomies and other procedures during labour are commonly reported by women in several countries, and often highlighted in birth activism. Yet, forced caesarean sections aside, the ethics of consent during labour has received little attention. Focusing on episiotomies, this paper addresses whether and how consent in labour should be obtained. We briefly review the rationale for informed consent, distinguishing its intrinsic and instrumental relevance for respecting autonomy. We also emphasise two non-explicit ways of giving consent: implied and opt-out consent. We then discuss challenges and opportunities for obtaining consent in labour and birth, given its unique position in medicine. We argue that consent for procedures in labour is always necessary, but this consent does not always have to be fully informed or explicit. We recommend an individualised approach where the antenatal period is used to exchange information and explore values and preferences with respect to the relevant procedures. Explicit consent should always be sought at the point of intervening, unless women antenatally insist otherwise. We caution against implied consent. However, if a woman does not give a conclusive response during labour and the stakes are high, care providers can move to clearly communicated opt-out consent. Our discussion is focused on episiotomies, but also provides a useful starting point for addressing the ethics of consent for other procedures during labour, as well as general time-critical medical procedures. 

 

Consent and the problem of epistemic injustice in obstetric care
Commentary
J Y Lee
Journal of Medical Ethics, 30 August 2023
Excerpt
An episiotomy is ‘an intrapartum procedure that involves an incision to enlarge the vaginal orifice,’1 and is primarily justified as a way to prevent higher degrees of perineal trauma or to facilitate a faster birth in cases of suspected fetal distress. Yet the effectiveness of episiotomies is controversial, and many professional bodies recommend against the routine use of episiotomies. In any case, unconsented episiotomies are alarmingly common, and some care providers in obstetric settings often fail to see consent as necessary in context. In their article, ‘The ethics of consent during labour and birth: episiotomies,’ van der Pijl et al reiterate that consent is necessary for episiotomies. They specify, further, that the antenatal period is crucial for exchanging information, establishing trust between the birthing subject and provider, and exploring the birthing subject’s—rather than the care provider’s—values and preferences regarding episiotomies. They recommend an individualised approach, which would enable birthing subjects to choose how and when they want to give consent…

Capacity assessment during labour and the role of opt-out consent
Commentary
Kelsey Mumford
Journal of Medical Ethics, 30 August 2023
Excerpt
Previous studies investigating the extent to which pregnant persons retain decision-making capacity during labour have shown poor recall, a component of capacity, about consent processes during obstetric emergency procedures in 14%–49% of cases. As the feature article acknowledges, this does not mean that pregnant persons should be assumed to lack decision-making capacity during labour. Although pain, labour intensity, exhaustion and medications can make consenting processes during labour more difficult and it is possible that these factors will result in the impaired ability of the pregnant person to make informed and voluntary decisions about treatment options, this possibility of impaired capacity should not be taken as the expected outcome nor should it be used as an excuse to skip consenting procedures. The default to treat labouring patients as able to make their own decisions still stands…

Episiotomies and the ethics of consent during labour and birth: thinking beyond the existing consent framework
Commentary
Anna Nelson, Beverley Clough
Journal of Medical Ethics, 30 August 2023
Excerpt
We agree with van der Pijl et al that the question of how to ensure consent is obtained for procedures which occur during labour and childbirth is vitally important, and worthy of greater attention. However, we argue that the modified opt-out approach to consent outlined in their paper may not do enough to protect the choice and agency of birthing people. Moreover, while their approach reflects a pragmatic attempt to facilitate legal clarity and certainty in this context, this is not necessarily responsive to the messy realities of decision-making during labour (and beyond). We outline some of our concerns with their proposals and demonstrate how these illuminate some broader, longstanding tensions around consent and medical law…

Birth, trust and consent: reasonable mistrust and trauma-informed remedies
Commentary
Elizabeth Lanphier, Leah Lomotey-Nakon
Journal of Medical Ethics, 30 August 2023
Excerpt
    In ‘The ethics of consent during labour and birth: episiotomies,’ van der Pijl et al respond to the prevalence of unconsented procedures during labour, proposing a set of necessary features for adequate consent to episiotomy. Their model emphasises information sharing, value exploration and trust between a pregnant person and their healthcare provider(s). While focused on consent to episiotomy, van der Pijl et al contend their approach may be applicable to consent for other procedures during labour and beyond pregnancy-related care.
One feature of their model for adequate informed consent is trust in the systems in which prenatal and labour and delivery care are provided. Yet, for some pregnant persons, mistrust in health systems is a reasonable sequela of experiences like racism and epistemic injustice. For a programme in which trust is central to adequate consent, it is important to identify—and counter—forms of mistrust toward pregnant persons within healthcare and acknowledge and rectify reasonable mistrust of pregnant persons toward healthcare…

Extending the ethics of episiotomy to vaginal examination: no place for opt-out consent
Commentary
Rebecca Brione
Journal of Medical Ethics, 30 August 2023
Excerpt
   van der Pijl et al argue that if ‘stakes are high’ and there is ‘clear conviction by the care provider’ that it is ‘necessary’, episiotomy may be given after ‘opt-out consent’. Here I caution against the applicability of their approach to vaginal examination (VE): another routine intervention in birth to which they suggest their discussion may apply. I highlight three concerns: first, the subjective and unjustified nature of assessments of ‘necessity’; second, the inadequacy of current consent practices in relation to VE; and third, the significant risk of perpetuating under-recognised harms associated with unwanted or unconsented VE. I argue that opt-out consent cannot be ethically justified for VE. Its use would result in further weakening of consent practices, circumvention of individuals’ autonomy, and greater harm for women and birthing people.
At the outset, it is important to recognise that the authors do not claim that their approach should be applied to VE, merely that their discussion may have relevance to consent for other interventions beyond episiotomy ‘where consent is also frequently lacking, and which are under-researched’, including VE.1 Nonetheless, it is easy to assume that episiotomy and VE are sufficiently similar that their analysis might be transferred wholesale. I disagree…

Safeguards for procedural consent in obstetric care
Commentary
David I Shalowitz, Steven J Ralston
Journal of Medical Ethics, 30 August 2023
Excerpt
Van der Pijl et al outline data suggesting an alarmingly high incidence of violation of the bodily integrity of patients in labour, including episiotomies performed without patients’ consent, or over their explicit objection.1 Similar data have been reported from the USA and Canada. The authors appropriately conclude that explicit consent is required at the time of all invasive obstetrical procedures, including episiotomy. Commonsense adjustments to the duration and detail of consent under conditions of clinical urgency are appropriate and should be familiar to any clinician involved in perinatal care, as well as non-obstetric proceduralists caring for acutely ill patients. However, complete omission of consent for any of these procedures is both disrespectful to patients’ autonomy and strongly associated with morbidity from birth-related psychosocial trauma…

Informed decision-making in labour: action required
Commentary
Gordon M Stirrat
Journal of Medical Ethics, 30 August 2023
Excerpt
    The timely feature article by van der Pijl et al 1 highlights not only the widespread frequency with which unconsented episiotomies and other procedures during labour are reported by women but also that there is hardly any discussion in the literature on the ethics of consent for procedures in labour. Those national and international bodies with responsibility for midwifery and obstetric practice need not only to recognise but also act to remedy this unacceptable situation.
The studies quoted used the recollection of women in reporting consent or lack of it and, although this is an entirely appropriate measure, it gives no insight into what, if any, informed decision-making the care providers carried out. Such information would be useful to determine how better practice might be achieved. A study into the practice of episiotomies by Dutch midwives and obstetricians is referred to and is not reassuring.2 They frequently expressed surprise that consent should be necessary and women were minimally involved in the decision for performing episiotomy. This and other examples quoted of lack of valid consent have a corrosive effect on the fundamental but fragile trust and necessary trustworthiness of the relationship between the person being cared for…

Setting a human rights and legal framework around ‘the ethics of consent during labour and birth: episiotomies’
Commentary
Bashi Kumar-Hazard, Hannah Grace Dahlen
Journal of Medical Ethics, 30 August 2023
Excerpt
    We commend the authors for their comprehensive discussion on consent and episiotomies. They correctly observe that informed consent for all proposed interventions in maternity care is always necessary. The claim that consent for maternity health services does not always have to be fully informed or explicit, however, is erroneous. We are especially concerned with, and surprised by, the endorsement of ‘opt-out consent’. ‘Opt-out consent’ (a.k.a. substitute decision making) is already standard practice in maternity healthcare, with obstetric violence a normalised response to conclusive refusals or requests for explanations.
Informed consent is based on the fundamental human rights to bodily autonomy and integrity, which healthcare providers are obliged to respect. Healthcare structured around human rights violations is not care. It is cruel and inhumane treatment—a violation of yet another fundamental human right—and a reflection of poor-quality care. To be valid, consent must always be informed, specific, timely, freely given and reversible. The provider must provide information specific to each and every proposed intervention in a timely manner. The consumer has the right to consider, freely accept or refuse before providers can act. They can also change their mind at any time…

Consent and episiotomies: do not let the perfect be the enemy of the good
Commentary
Elselijn Kingma, Marit van der Pijl, Corine Verhoeven, Martine Hollander, Ank de Jonge
Journal of Medical Ethics, 30 August 2023
Excerpt
… Neither informed consent alone, nor our proposal, can solve every problem in maternity care. Commenting authors noted several limitations and further challenges. But nearly all agree our proposal is a very significant and realistic step in the right direction, which can significantly improve the situation for vast numbers of women and healthcare providers. We particularly emphasise the importance of multilevel institutional support and ongoing education in its implementation and want to draw attention to our original discussion of the intrinsic value of asking consent: this retains significant value even among many other shortcomings and (perhaps especially) power differences. Our practising healthcare providers, finally, emphasise that within the reality of a busy maternity ward there are very many challenges. We should not let the perfect be the enemy of what nearly all commentators agree is a very significant improvement, which has potential for (well researched and suitably modified) application to other interventions in labour.

Spotlight Articles

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In this issue’s Spotlight section we include two recent articles analyzing the structure and components of ICFs [informed consent forms].

In Characterization of Key Information Sections in Informed Consent Forms Posted on ClinicalTrials.gov published in the Journal of Clinical Translational Science the authors assess the presence, length, readability and other parameters of KIs [key information sections] in ICFs posted on ClinicalTrials.gov in alignment with the revised Common Rule. The authors argue that “…widely adopted guidelines could also facilitate compliance analyses that are currently challenged by the broad subjectivity in interpreting the KI requirement [in the revised Common Rule].”

In the Perspectives in Clinical Research article Redefining informed consent form in cell and gene therapy trials, Dalal et at. address the need to adapt the informed consent process and ICFs to the unique context of gene therapy trials [see Fig 3 below] as well as the  cultural contexts in which the trials are implemented.

 

Characterization of Key Information Sections in Informed Consent Forms Posted on ClinicalTrials.gov
Luke Gelinas, Walker Morrell, Tony Tse, Ava Glazier, Deborah A. Zarin, Barbara E. Bierer
Journal of Clinical and Translational Science, 14 August 2023
Abstract
Introduction
Recent revisions to the United States Federal Common Rule governing human studies funded or conducted by the federal government require the provision of a “concise and focused” key information (KI) section in informed consent forms (ICFs). We performed a systematic study to characterize KI sections of ICFs for federally-funded trials available on ClinicalTrials.gov.
Methods
We downloaded ICFs posted on ClinicalTrials.gov for treatment trials initiated on or after the revised Common Rule effective date. Trial records (n=102) were assessed by intervention type, study phase, recruitment status, and enrollment size. The ICFs and their KI sections, if present, were characterized by page length, word count, readability, topic, and formatting elements.
Results
Of the 102 trial records, 76 had identifiable KI sections that were, on average, 10% of the total length of full ICF documents. KI readability grade level was not notably different than other sections of ICFs. Most KI sections were distinguished by section headers and included lists but contained few other formatting elements. Most KI sections included a subset of topics consistent with the basic elements of informed consent specified in the Common Rule.
Conclusion
Many of the KI sections in the study sample aligned with practices suggested in the preamble to the revised Common Rule. Further, our results suggest that some KI sections were tailored in study-specific ways. Nevertheless, guidelines on how to write concise and comprehensible KI sections would improve the utility and readability of KI sections.

Redefining informed consent form in cell and gene therapy trials
Review Article
Varsha Dalal, Geeta Jotwani, Munna Lal Yadav
Perspectives in Clinical Research, 28 July 2023
Abstract
Informed consent is a foundation of the ethical conduct of research involving human participants. Based on the ethical principle of respect for persons, the goal of informed consent is to ensure that participants are aware of the risks and potential benefits and make a voluntary decision about participating in clinical trial research. The extraordinary scientific advances happening globally have demonstrated the potential of regenerative therapies in transforming the health of the nation by providing a therapeutic option for diseases that were previously considered incurable. These therapies, which include cells and gene therapy (GT) labeled as Advanced Therapeutic Medicinal Products globally, have complex mechanisms of action. Owing to their highly personalized and intricate nature of these therapies, developing the latter often presents unique challenges above and beyond those encountered for small molecule drugs. We recently looked through some cell and GT clinical trials and realized the lacunae in the informed consent form (ICF) provided by the investigators. Especially in a country like India, where the general understanding and perception of patients is limited regarding clinical trials, it is felt that any lapses in the consent process may jeopardize the informed decision‑making and safety of the participants and tarnish the reputation of India globally. The present article highlights the need for appropriate patient and public education on the various aspects of cell and gene therapies and aims to address all the elements of ICF in light of the challenges associated with these innovative therapies.