Ethics of Adaptive Designs for Randomized Controlled Trials.

Over recent decades, adaptive trial designs have been used more and more often for clinical trials, including randomized controlled trials (RCTs). This rise in the use of adaptive RCTs has been accompanied by debates about whether such trials offer ethical and methodological advantages over traditional, fixed RCTs. This study examined how experts on clinical trial methods and ethics believe that adaptive RCTs, compared to fixed ones, affect the ethical character of clinical research. We conducted in-depth interviews with 17 researchers from bioethics, epidemiology, biostatistics, and/or medical backgrounds. While about half believed that adaptive trials are more complex and may thus threaten autonomy, these respondents also expressed that this challenge is not insurmountable. Most respondents expressed that efficiency and potential for participant benefit were the main justifications for adaptive trials. There was tension about whether adaptive randomization in response to increasing information disrupts clinical equipoise, with some respondents insisting that uncertainty still exists and therefore clinical equipoise is not disrupted. These findings suggest that further discussion is needed to increase the awareness and utility of these study designs.

Managing community engagement in research in Uganda: insights from practices in HIV/AIDS research.

BACKGROUND: Community engagement (CE) in research is valuable for instrumental and intrinsic reasons. Despite existing guidance on how to ensure meaningful CE, much of what it takes to achieve this goal differs across settings. Considering the emerging trend towards mandating CE in many research studies, this study aimed at documenting how CE is conceptualized and implemented, and then providing context-specific guidance on how researchers and research regulators in Uganda could think about and manage CE in research. METHODS: We conducted qualitative interviews and focus group discussions involving forty-one respondents who were experienced in HIV/AIDS biomedical research involving CE. Thirty-eight of these were directly or indirectly associated with Uganda's leading research institution in the field of HIV/AIDS. They included Principal Investigators, Community Liaisons Officers, Research Ethics Committee members and Community Advisory Board Members. Three respondents were from Uganda National Council for Science and Technology. Data were collected between August 2019 and August 2020, using audio-taped focus group discussions and key informant interviews, transcribed and analyzed manually to generate themes and subthemes. RESULTS: Three major themes emerged: goals or value of CE; the means of CE, and, the evaluation of CE. Goals or value of CE generated four subthemes representing the overarching goals of CE: (1) Promote communities' agency; (2) Generate and sustain trust; (3) Protect and promote communities' rights and interests; and, (4) Help studies optimize participation in the form of enrolment and retention of participants. What usually comes under the nomenclatures of methods, strategies, and approaches of CE, such as town-hall meetings, sports events, drama, and the like, should simply be understood as the means of CE, and it is not desirable to hold pre-conceived and fixed ideas about the best means to conduct CE in research since a lot depend on the context. Finally, the study found that despite CE's critical importance, which suggests the need to track and evaluate it, CE is currently intermittently evaluated, and for inadequate motivations. CONCLUSIONS: Existing guidance on how to conduct robust CE in research is no substitute for creativity, flexibility, and reflexivity on the part of both researchers and research regulators.

Learning Health Care and the Obligation to Participate in Research.

This commentary responds to the article "Compulsory Research in Learning Health Care: Against a Minimal Risk Limit," by Robert Steel. Steel acknowledges that our ethics framework for a learning health care system, published in the 2013 special report Ethical Oversight of Learning Health Care Systems , includes an obligation on the part of patients to participate in learning activities, but he argues that this obligation does not go far enough. Steel, who provides an interesting justification for compulsory research participation in learning health care, claims that our obligation is limited to only minimal risk research. We take exception to that characterization insofar as it detracts from what we believe is most relevant for assessing learning activities, which is how much additional risk and burden a learning activity poses compared to clinical care alone. We also clarify that the level of additional risk is not the only morally relevant consideration in determining if a learning activity should be compulsory. Also important is whether the learning activity includes interventions or choices that engage values of importance to patients.

Treating Workers as Essential Too: An Ethical Framework for Public Health Interventions to Prevent and Control COVID-19 Infections among Meat-processing Facility Workers and Their Communities in the United States.

Meat is a multi-billion-dollar industry that relies on people performing risky physical work inside meat-processing facilities over long shifts in close proximity. These workers are socially disempowered, and many are members of groups beset by historic and ongoing structural discrimination. The combination of working conditions and worker characteristics facilitate the spread of SARS-CoV-2, the virus that causes COVID-19. Workers have been expected to put their health and lives at risk during the pandemic because of government and industry pressures to keep this "essential industry" producing. Numerous interventions can significantly reduce the risks to workers and their communities; however, the industry's implementation has been sporadic and inconsistent. With a focus on the U.S. context, this paper offers an ethical framework for infection prevention and control recommendations grounded in public health values of health and safety, interdependence and solidarity, and health equity and justice, with particular attention to considerations of reciprocity, equitable burden sharing, harm reduction, and health promotion. Meat-processing workers are owed an approach that protects their health relative to the risks of harms to them, their families, and their communities. Sacrifices from businesses benefitting financially from essential industry status are ethically warranted and should acknowledge the risks assumed by workers in the context of existing structural inequities.

Streamlined versus traditional consent for low-risk comparative effectiveness trials: a randomized experimental study to measure patients' and public attitudes.

Aim: Streamlining consent for low-risk comparative effectiveness research (CER) could facilitate research, while safeguarding patients' rights. Materials & methods: 2618 adults were randomized to one of seven consent approaches (six streamlined and one traditional) for a hypothetical, low-risk CER study. A survey measured understanding, voluntariness, and feelings of respect. Results: Participants in all arms had a high understanding of the trial and positive attitudes toward the consent interaction. Highest satisfaction was with a streamlined approach showing a video before the medical appointment. Participants in streamlined were more likely to mistakenly think a signature was required. Conclusion: Streamlined consent was no less acceptable than traditional, signed consent. Streamlined and traditional approaches achieved similar levels of understanding, voluntariness and a feeling that the doctor-patient interaction was respectful.

Randomized comparison of two interventions to enhance understanding during the informed consent process for research.

BACKGROUND/AIMS: Many investigators have tested interventions to improve research participant understanding of information shared during the informed consent process, using a variety of methods and with mixed results. A valid criticism of most consent research is that studies are often conducted in simulated research settings rather than ongoing clinical studies. The present study rigorously tested two simple and easily adoptable strategies for presenting key consent information to participants eligible to enroll in six actual clinical trials (i.e. six parent studies). METHODS: In collaboration with the study team from each parent study, we developed two consent interventions: a fact sheet and an interview-style video. The content of each of the intervention was based on the information shared in the consent form approved for each parent study. Participants were randomized to the standard consent process, or to one of the two interventions. Once exposed to the assigned consent mode, participants were asked to complete an assessment of understanding. The study was powered to determine whether those exposed to the fact sheet or video performed better on the consent assessment compared to those exposed to the standard consent. We also assessed participant satisfaction with the consent process. RESULTS: A total of 284 participants were randomized to one of the three consent arms. Assessments of understanding were completed with a total of 273 participants from July 2017 to April 2019. Participants exposed to the video had better understanding scores compared to those exposed to the standard consent form process (p value = 0.020). Participants were more satisfied with the video when compared to the standard consent. Participants who received the fact sheet did not achieve higher overall understanding or satisfaction scores when compared to the standard consent process. CONCLUSION: This randomized study of two novel consent interventions across six different clinical trials demonstrated a statistically significant difference in participant understanding based on overall scores among those exposed to the video intervention compared to those exposed to the standard consent.

What Factors Predict Willingness to Join Low-Risk Pragmatic Clinical Trials?

Pragmatic clinical trials (PCTs) may improve the efficiency, relevance, and representativeness of research. While prior research has indicated that willingness to join a PCT is high, it is not universal among those asked in surveys exploring attitudes toward hypothetical PCTs. The objective of this study was to examine what factors predict willingness to join a hypothetical low-risk PCT comparing two blood pressure medicines. In our study, 2,618 respondents, recruited from three populations (adult patients from an academic health system, adult patients from an integrated delivery system, and adults from an online nationally representative panel), completed an online survey. Most respondents (90%) expressed willingness to participate in the hypothetical PCT. The two key predictors of expressed willingness to join low-risk PCTs were respondents' understanding of key features of PCTs, including how they differ from traditional research, and the degree of importance respondents perceived comparative research to have. Increasing awareness of the rationale for PCTs and understanding of these trials, including how they differ from explanatory trials, may increase prospective participants' willingness to contribute to this effort.

The features and qualities of online training modules in research ethics: a case study evaluating their institutional application for the University of Botswana.

Research ethics remains a cornerstone of the scientific enterprise as it defines the boundaries of responsible conduct of research. Our aim was to systematically identify, review and test online training courses in research ethics which could be considered most appropriate for future training at the University of Botswana (UB). We used an evaluative tool that included both descriptive and evaluative criteria for assessing the strengths, weaknesses and appropriateness of 10 online research ethics courses which are publicly accessible. We then assembled Focus Group Discussions (FGDs) to engage the UB community to select the best 2-3 online courses that are considered most suited for use in future training of research ethics at UB. Twenty respondents participated in three FGDs. Our findings show that there is limited research ethics training capacity in low resourced academic institutions like UB. Online training opportunities could be used to address this challenge. Our analysis reveal that out of the 10 online courses reviewed, CITI program, Family Health International, and Training and Resource in Research Ethics Evaluation have characteristics that would make them suitable for utilization in Botswana. We believe the findings from this case study will be of value to other similarly situated research institutions.

Investigator Disclosure and Advanced Cancer Patient Understanding of Informed Consent and Prognosis in Phase I Clinical Trials.

PURPOSE: Advanced cancer patients (ACPs) who participate in phase I clinical trials often report a less-than-ideal understanding of the required elements of informed consent (IC) and unrealistic expectations for anticancer benefit and prognosis. We examined phase I clinical trial enrollment discussions and their associations with subsequent ACP understanding. METHODS: Clinical encounters about enrollment in phase I trials between 101 ACPs and 29 oncologists (principal investigators [PIs] and fellows) at three US academic medical institutions were recorded. The Roter Interaction Analysis System was used for analysis. ACPs completed follow-up questionnaires to assess IC recall. RESULTS: PIs disclosed the following phase I IC elements to ACPs in encounters: trial purpose in 40%; specific physical risks in 60%; potential specific medical benefits gained by trial participation (eg, disease stabilization) in 48.2%; and alternatives to phase I trial participation in 47.1%, with 1.1% of encounters containing palliative and 2.3% hospice information. PIs provided ACP-specific prognoses in 29.0% of encounters but used precise terms of death in only 4.7% and terminal in 1.2%. A significant association existed between PI disclosure of the trial purpose as dosage/toxicity, and ACPs subsequently correctly recalled trial purpose versus PIs who did not disclose it (85% v 13%; P < .05). CONCLUSION: Many oncologists provide incomplete disclosures about phase I trials to ACPs. When disclosure of certain elements of IC occurs, it seems to be associated with better recall, especially with regard to the research purpose of phase I trials.

Ethical challenges in research on post-abortion care with adolescents: experiences of researchers in Zambia.

Post-abortion care (PAC) research is increasingly being conducted in low- and middle-income countries (LMICs) to help reduce the high burden of unsafe abortion. This study aims to help address the evidence gap about ethical challenges that researchers in LMICs face when carrying out PAC research with adolescents. Employing an explorative qualitative approach, the study identified several ethics challenges encountered by PAC researchers in Zambia, including those associated with seeking ethics and regulatory approvals at institutional and national levels. Persistent stigma around abortion and community perceptions that PAC studies encourage adolescents to seek abortion affected adolescents' right to exercise their autonomy and to make decisions as well as exposed adolescents to social stigmatization risks. Challenges with recruitment was reported to result in abandoning of studies, thereby undermining development of PAC services that are more responsive to adolescent needs. Training needs identified included knowledge of best practices for conducting and disseminating PAC research. Strategies for addressing the ethical challenges included trust building and using less value-laden terminology when seeking permission and consent. It is essential to the future of PAC research in Zambia and globally that these important challenges be addressed through the development of comprehensive ethics guidance.

Stakeholder perspectives regarding alternate approaches to informed consent for comparative effectiveness research.

INTRODUCTION: Traditional informed consent approaches, involving separate discussions and lengthy consent forms, may be an imperfect fit for comparative effectiveness research (CER) that is integrated into usual care and compares non-investigational treatments. However, systematic efforts to collect broad stakeholder perspectives about alternative streamlined approaches to disclosure and consent in this context have been limited. METHODS: We used a deliberative engagement method to solicit the views of a multi-stakeholder group regarding 3 alternative models of disclosure, consent, and authorization in CER studies: Opt-In, Opt-Out, and "General Approval". Participants considered the acceptability of these 3 models for observational and randomized CER studies of hypertension medications and for alternative treatments for spinal stenosis, all conducted in the context of a learning health care system. RESULTS: Fifty-eight stakeholders participated in the all-day deliberative engagement session. Following deliberation, a majority of stakeholders (67%) liked the General Approval model for the observational hypertension study, more than the number who reported liking Opt-Out or Opt-In (45% and 36%, respectively). Support was lower for General Approval model in the context of a randomized hypertension study, with 80% liking a traditional Opt-In approach, compared with 54% liking Opt-Out, and 11% liking General Approval. Similarly, for the spinal stenosis CER studies, while most stakeholders preferred a streamlined Opt-Out approach for the observational design, most preferred a traditional Opt-In approach for the randomized version. CONCLUSIONS: This multi-stakeholder group was more favorable towards streamlined models for disclosure and authorization for observational CER than randomized designs. These findings are consistent with arguments that informed consent requirements should be tailored to the context of the research design, rather than a standard "one size fits all" approach.

Ethics and Learning Health Care: The Essential roles of engagement, transparency, and accountability.

Extraordinary innovation in medicine promises vast improvements to the health of individuals and communities. Yet it is a lost opportunity that data from most medical care is never aggregated or analyzed. Even when data are aggregated and analyzed, most of this "learning" is never translated into improved practice. The Learning Health Care System (LHCS) is a response to both of these challenges. Ethically, the LHCS relies on a foundational understanding between patients and their health systems in which patients endorse the use of their data for ongoing learning, and health systems commit to improving care based on what is learned. We have outlined elsewhere a set of seven ethical obligations for Learning Health Care, including the obligation to respect the rights and dignity of patients. In this paper, we suggest that three specific respect-promoting actions are morally required in a LHCS: engagement with patients about ongoing learning activities, transparency with patients about ongoing learning activities, and accountability in implementing what is learned.

How are PCORI-funded researchers engaging patients in research and what are the ethical implications?

BACKGROUND: Despite growing interest in patient engagement in research, there are few empirical investigations of the nature of engagement and its effects. This information is important, not only to inform practical decisions researchers and funders must make, but also to inform discussion of the ethical implications of engaging patients, which has received little attention to date. METHODS: The aim of this study was to characterize patient engagement in research funded by the Patient-Centered Outcomes Research Institute (PCORI) as a step toward enhancing current understanding of the nature and effects of engagement and prompting an in-depth consideration of the ethical implications of engaging patients in research. Qualitative interviews were conducted with 19 PCORI-funded principal investigators and with 33 patients engaged in 18 of the same 19 projects. RESULTS: Reasons cited for engaging patients included to enhance relevance and feasibility and to improve dissemination. While engagement occurred at different points during the research, patients were most commonly engaged in reviewing study materials and less commonly engaged at earlier points. Engagement varied by approach, frequency of interaction, and the extent to which patient input changed the research. Impacts of engagement included improving the relevance, feasibility, acceptability, and quality of the research. CONCLUSION: Our findings on the nature and impacts of engagement have importance not only for practical questions researchers, funders, and patients might raise, but also for several ethical considerations regarding patient engagement related to why patients are engaged, the kinds of patients engaged, when patients are engaged, and how patients are engaged. We discuss our findings in consideration of the main ethical issues they imply, including ethical rationales for engagement, justice-related concerns, and ethical concerns arising from when and how patients are engaged. As efforts to engage patients increase, this discussion provides insights that researchers, funders, and patients may find valuable.

A Journey in Public Health Ethics.

While medical ethics has a long history, and research ethics guidance emerged more formally in the 1960s and 1970s, frameworks for public health ethics began to appear in the 1990s. The author's thinking about public health ethics evolved from consideration of some of the ethics and policy questions surfacing regularly in the HIV/AIDS epidemic. This essay discusses some of the shared commitments of public health and ethics, as well as how one might apply an ethics lens to public health programs, both generally and in the contexts of public health preparedness and obesity prevention.

Patient engagement in patient-centered outcomes research: challenges, facilitators and actions to strengthen the field.

AIM: To describe challenges to and facilitators of patient engagement to inform future strategies and suggested actions to strengthen engagement. METHODS: Interviews with 19 principal investigators of projects funded by the Patient-Centered Outcomes Research Institute and with 33 patients from 18 of the 19 projects. RESULTS: Facilitators included using existing resources, having clear goals, educating patients and treating patients respectfully. Logistical challenges included extra time and work, institutional barriers and difficulty having meetings. Substantive challenges to selecting, educating and engaging patients, and incorporating feedback were also reported. CONCLUSION: To bolster the infrastructure for engagement, we suggest funders, institutions and researchers focus on resources and training for researchers and patients, networks and programs to connect stakeholders and model policies.

Deliberative Engagement Methods for Patient-Centered Outcomes Research.

There is growing emphasis on eliciting and incorporating stakeholder perspectives into health research and public policy development. The deliberative engagement session (DES) method provides one approach to elicit informed preferences from patients and other stakeholders on policy issues. DES involves day-long interaction with participants, including short plenary presentations followed by small group discussion. While interest in DES methods is expanding, practical guidance for researchers on this method remains limited. In this paper, we describe the DES method and its contemporary relevance for health policy research, illustrate how to conduct a DES using an example of a recent patient-centered outcomes research (PCOR) study with which we were involved, and discuss strengths and challenges of using this approach. DES methods generate rich data, reduce the risk of eliciting uniformed preferences or non-attitudes, and increase the likelihood of eliciting informed, reflective preferences. However, they are resource-intensive, and thus generally require trading away a larger, more representative sample. Despite these limitations, the DES method, when carefully designed, is well-suited for engaging stakeholders in research on complex health policy issues.

What allows a health care system to become a learning health care system: Results from interviews with health system leaders.

INTRODUCTION: The US health care system faces pressure to improve quality while managing complexity, curbing costs, and reducing inefficiency. These shortcomings have sparked interest in the Learning Health Care System (LHCS) as an alternate approach to organizing research and clinical care. Although diverse stakeholders have expressed support for moving toward an LHCS model, limited guidance exists for institutions considering such a transition. METHODS: Interviews were conducted with institutional leaders from 25 health care systems considered to be at the forefront of LHCS. Interviews focused on the process of transitioning toward an LHCS, including motivations for change, key components, challenges encountered, and strategies for success, and on ethics and regulatory issues encountered. Qualitative analysis identified key themes across institutions. RESULTS: Respondents described 5 themes related to the origin of their LHCS transformation: (1) visionary leadership or influence of a key individual, (2) adaptation to a changing health care landscape, (3) external funding, (4) regulatory or legislative influence, and (5) mergers or expansions. They described 6 challenges: (1) organizational culture, (2) data systems and data sharing, (3) funding learning activities, (4) limited supply of skilled individuals, (5) managing competing priorities, and (6) regulatory challenges. Finally, they suggested 8 strategies to support transformation: (1) strong leadership, (2) setting a limited number of organizational priorities, (3) building on existing strengths, (4) training programs, (5) "purposeful" design of data systems, (6) internal transparency of quality metrics, (7) payer/provider integration, and, within academic medical centers, (8) academic/clinical integration. CONCLUSIONS: Even institutions at the forefront of LHCS described the transition as difficult. Their experiences provide insight into other institutions considering similar transitions, including elements essential for success and likely challenges.

A randomized study of multimedia informational aids for research on medical practices: Implications for informed consent.

BACKGROUND/AIMS: Participant understanding is a key element of informed consent for enrollment in research. However, participants often do not understand the nature, risks, benefits, or design of the studies in which they take part. Research on medical practices, which studies standard interventions rather than new treatments, has the potential to be especially confusing to participants because it is embedded within usual clinical care. Our objective in this randomized study was to compare the ability of a range of multimedia informational aids to improve participant understanding in the context of research on medical practices. METHODS: We administered a web-based survey to members of a proprietary online panel sample selected to match national US demographics. Respondents were randomized to one of five arms: four content-equivalent informational aids (animated videos, slideshows with voice-over, comics, and text) and one no-intervention control. We measured knowledge of research on medical practices using a summary knowledge score from 10 questions based on the content of the informational aids. We used analysis of variance and paired t-tests to compare knowledge scores between arms. RESULTS: There were 1500 completed surveys (300 in each arm). Mean knowledge scores were highest for the slideshows with voice-over (65.7%), followed by the animated videos (62.7%), comics (60.7%), text (57.2%), and control (50.3%). Differences between arms were statistically significant except between the slideshows with voice-over and animated videos and between the animated videos and comics. Informational aids that included an audio component (animated videos and slideshows with voice-over) had higher knowledge scores than those without an audio component (64.2% vs 59.0%, p < .0001). There was no difference between informational aids with a character-driven story component (animated videos and comics) and those without. CONCLUSION: Our results show that simple multimedia aids that use a dual-channel approach, such as voice-over with visual reinforcement, can improve participant knowledge more effectively than text alone. However, the relatively low knowledge scores suggest that targeted informational aids may be needed to teach some particularly challenging concepts. Nonetheless, our results demonstrate the potential to improve informed consent for research on medical practices using multimedia aids that include simplified language and visual metaphors.