Ethical aspects of clinical trials: the attitudes of participants in two non-cancer trials

OBJECTIVES: To investigate attitudes to clinical trials in non-cancer trial participants. DESIGN: Questionnaires at entry, during, and after participation in a clinical study. SETTING: Participants in: (i) ROC: a clinical study comparing systemic interferon-alpha-2A treatment vs. prednisolone enemas in ulcerative colitis; and (ii) MRCRUC: a clinical study investigating low-field magnetic resonance imaging as a new modality for the evaluation of patients with inflammatory bowel disease. SUBJECTS: Thirty-two patients in ROC and 47 patients in MRCRUC. OUTCOME MEASURES: Attitudes towards different aspects of clinical research. RESULTS: The majority found scientific testing of clinical methods necessary, having positive attitudes towards both participation by themselves and others. The creation of a personal moral problem by denying participation was rejected by a large majority, and still both personal and altruistic motives for participation were highly rated. An important motive for accepting inclusion was the expectation of being 'a special patient' during the trial. The presence of research ethics committees controlling clinical research had a significant positive impact on decisions to participate, and drawing lots and blinding were found problematic by only a minority. Patients valued their satisfaction with participation in the trials highly, and would almost all accept a request to participate in future trials. The most important reason for this was a feeling of receiving better care and information than expected outside a trial setting, primarily determined by the patients seeing only one physician during the trials. A pronounced wish to obtain follow-up information was expressed. CONCLUSION: Attitudes towards medical research are positive with both altruistic and nonaltruistic motives for participation. Expectations of being treated as 'a special patient' in the trial were important in accepting to participate. Seeing the same physician at control visits was an important factor for satisfaction with participation.     

Attitudes towards clinical research amongst participants and nonparticipants

OBJECTIVES: To investigate attitudes to clinical research amongst cancer trial participants and nonparticipants, and to compare results with those from previous studies amongst participants in noncancer trials. DESIGN: Trial participating respondents were given three questionnaires during the clinical trials. Respondents amongst patients declining randomization answered a single questionnaire. SETTING: Participants and nonparticipants in randomized clinical cancer trials. SUBJECTS: Forty-one participants and 47 nonparticipants in cancer trials. RESULTS: Altruistic motives of physicians to conduct medical research were highly rated. Attitudes towards clinical research were positive in all groups, with nonparticipant respondents being the least positive. Eight to nine tenths found scientific testing necessary before general health service implementation. Trial participants were, as compared with nonparticipating respondents, more positive towards both participation of self and others. Both personal and altruistic motives for participation were highly rated. Primary reasons for nonparticipation were fear of 'the unknown' and/or unease with randomization. Only a minority felt a moral problem created by declining trial participation. Respondents amongst noncancer participants were more satisfied with the information given than both cancer participants and cancer nonparticipants. Negative experiences in cancer participants generally dealt with frustration related to seeing too many physicians at check-up appointments. CONCLUSION: Attitudes towards clinical research are generally positive even in cancer nonparticipants. Both personal and altruistic motives for participation were highly rated. A fear of 'the unknown' and resentments towards randomization were primary reasons to renounce participation. Seeing too many physicians at check-up appointments seems to be an important factor for negative experiences in cancer trial participants.     

Using perceptual mapping methods to understand gender differences in perceived barriers and benefits of clinical research participation in urban minority HIV+ patients

Minority participation in HIV clinical trials research is critical to understanding the impact of medications or behavioral interventions, but little is known about gender differences in perceptions of participation. We surveyed 50 minority HIV+ patients from an urban clinic to assess perceived risks/benefits of clinical trial research participation and used innovative marketing methods to analyze results. Perceptual mapping and vector message-modeling, a method that creates 3-D models representing how groups conceptualize elements, were used to assess how male and female participants could be motivated to participate. Results showed men farther away from participation and more concerned with HIV disclosure and experimentation than women. Men expressed distrust of the medical system, doubted HIV's origin, and knew less about research implementation. Women were closer to participation in both behavior and medical trials and perceived medication issues as more significant, including fear of losing medication stability, medications not working, being in the placebo group, and experiencing side effects. Vector modeling shows that messages would need to focus on different aspects of clinical research for men and women and that interventions aimed at minority HIV+ patients to encourage clinical trial participation would need to be targeted to their unique perceptions. Understanding gender perceptions of HIV clinical research has significant implications for targeting messages to increase minority participation.     

Ethical aspects of clinical trials: the attitudes of the public and out-patients

OBJECTIVES: To investigate attitudes to clinical research amongst potential research participants. DESIGN: Questionnaire-survey. SETTING: Two medical out-patient clinics and the background population. SUBJECTS: A total of 508 randomly selected citizens in Copenhagen County (64% responded) and 200 consecutive patients attending the out-patient clinics (64% responded). OUTCOME MEASURES: Attitudes toward different aspects of clinical research. RESULTS: Positive attitudes toward medical research were disclosed. The majority found scientific testing necessary, although only a minority considered participation a moral obligation. Both personal benefits and altruistic motives for participation were highly rated, whereas former positive experiences from trial participation had only minor impact on decisions. Several respondents stated former trial participation had changed their attitudes negatively. Lack of feedback of results was of major importance for this change. Attitudes are significantly influenced by the presence of independent research ethics committees, whereas trial technicalities such as drawing lots and blinding was found problematic by only a few respondents. Altruistic motives of physicians to conduct trials were highly rated by a majority of respondents, but the motive of promoting doctors' careers was also judged important. Respondents rated nondiscomforting procedures as acceptable or having only a small impact or strain on their lives. CONCLUSION: Attitudes toward medical research are positive amongst out-patients and the general public. Altruistic and nonaltruistic motives both concerning trial participation and concerning the motives of physicians to conduct medical research were rated highly. Lack of feedback concerning results of trials to participants was important for a negative change in attitude toward participation.     

Clinical trials in children

The imperative to undertake randomised trials in children arises from extraordinary advances in basic biomedical sciences, needing a matching commitment to translational research if child health is to reap the benefits from this new knowledge. Unfortunately, many prescribed treatments for children have not been adequately tested in children, sometimes resulting in harmful treatments being given and beneficial treatments being withheld. Government, industry, funding agencies, and clinicians are responsible for research priorities being adult-focused because of the greater burden of disease in adults, coupled with financial and marketing considerations. This bias has meant that the equal rights of children to participate in trials has not always been recognised. This is changing, however, as the need for clinical trials in children has been increasingly recognised by the scientific community and broader public, leading to new legislation in some countries making trials of interventions mandatory in children as well as adults before drug approval is given. Trials in children are more challenging than those in adults. The pool of eligible children entering trials is often small because many conditions are uncommon in children, and the threshold for gaining consent is often higher and more complex because parents have to make decisions about trial participation on behalf of their child. Uncertain about what is best, despite supporting the notion of trials in principle, parents and paediatricians generally opt for the new intervention or for standard care rather than trial participation. In this review, we explore issues relating to trial participation for children and suggest some strategies for improving the conduct of clinical trials involving children.     

The clinician as investigator: participating in clinical trials in the practice setting

The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of trials needed to properly evaluate them. The majority of patients treated today, many of whom could be eligible for participation in these studies, are seen in community hospitals and medical practices that are not affiliated with an academic medical center. Thus, there is a demonstrable need for physicians in private practice to enlist as investigators in these trials. This article is intended to encourage those physicians by describing the need and providing the rationale for their participation. It covers basic requirements for participating in clinical trials and outlines ethical, regulatory, financial, and other logistical issues of importance for the potential investigator and provides an algorithm for selecting a study for participation. Finally, the appendices review basic elements of study design and statistical principles, which may be of interest to a potential investigator.     

Understanding and Overcoming the Challenges Related to Cardiovascular Trials Involving Patients with Kidney Disease

Cardiovascular disease is a prevalent and prognostically important comorbidity among patients with kidney disease, and individuals with kidney disease make up a sizeable proportion (30%–60%) of patients with cardiovascular disease. However, several systematic reviews of cardiovascular trials have observed that patients with kidney disease, particularly those with advanced kidney disease, are often excluded from trial participation. Thus, currently available trial data for cardiovascular interventions in patients with kidney disease may be insufficient to make recommendations on the optimal approach for many therapies. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, convened a multidisciplinary, international work group and hosted a stakeholder workshop intended to understand and develop strategies for overcoming the challenges with involving patients with kidney disease in cardiovascular clinical trials, with a particular focus on those with advanced disease. These efforts considered perspectives from stakeholders, including academia, industry, contract research organizations, regulatory agencies, patients, and care partners. This article outlines the key challenges and potential solutions discussed during the workshop centered on the following areas for improvement: building the business case, re-examining study design and implementation, and changing the clinical trial culture in nephrology. Regulatory and financial incentives could serve to mitigate financial concerns with involving patients with kidney disease in cardiovascular trials. Concerns that their inclusion could affect efficacy or safety results could be addressed through thoughtful approaches to study design and risk mitigation strategies. Finally, there is a need for closer collaboration between nephrologists and cardiologists and systemic change within the nephrology community such that participation of patients with kidney disease in clinical trials is prioritized. Ultimately, greater participation of patients with kidney disease in cardiovascular trials will help build the evidence base to guide optimal management of cardiovascular disease for this population.     

Predicting Product Adherence in a Topical Microbicide Safety Trial in Pune, India

The inconclusive results of past trials and recent findings of partial protection of Tenofovir 1% gel underscore the need to better understand product adherence in microbicide trials. This study aimed to identify factors predicting couples' ability to sustain topical gel and condom use during clinical trial participation. We enrolled 100 Indian participants of a randomized, controlled safety trial of Tenofovir 1% gel (CT cohort) and 100 similar women who were ineligible or declined trial participation (NCT cohort). Compared to the NCT cohort, CT women reported higher baseline condom use, more positive attitudes towards condoms and higher levels of protection efficacy. While NCT condom use remained low, CT condom use increased dramatically during the study. Reported gel consistency was higher than condom consistency. Individual and couple-related factors predicted condom consistency and interest in future gel use, but not gel consistency. Findings could inform trial recruitment strategies and product introduction.     

Minority HIV patients' perceptions of barriers and facilitators to participation in clinical research

HIV clinical trials play an essential role in producing new HIV medications, developing guidelines for the appropriate timing of antiretroviral treatment, and evaluating behavioral interventions that aim to increase the quality of life of HIV-infected individuals. It is critical to have participation from all demographic groups, yet minorities are disproportionately underrepresented in HIV clinical research. This study assessed HIV+ minority patient perceptions of the barriers and benefits of participating in HIV clinical trials in an HIV clinic of a large, urban teaching hospital. Twenty-six, age-eligible (18-65), minority patients were recruited and participated in three focus groups, separated by clinical research participation status. Results suggest differences in perceptions between those who had and had not participated. Facilitators for those who had participated included doctor recommendation and receiving extra medical attention. Those who had not participated indicated disclosure of HIV status, fear of losing the stability that their current medication regimen provided, distrust of the medical system and doubt about the origin of HIV were major deterrents of participation. Both groups indicated a need to better educate minority patients about what clinical research is and its benefits. To increase minority participation, it is vital to examine the perceptions of minority HIV-infected patients and develop culturally competent, developmentally appropriate messages that address these barriers.     

Computers in rheumatology practice: implications for clinical research

We conducted a survey to determine the current and potential uses of computerized information systems in clinical rheumatology. One in 3 rheumatologists currently uses an office based computer, primarily for administrative functions, and at least one in 5 is likely to acquire a computer in the near future. Survey responses indicate that the increased use of office based computers will increase the willingness of community practitioners to participate in clinical research. This development will provide an opportunity to broaden the scope of clinical research participation and to increase the pool of patients available for cooperative clinical trials in rheumatology.     

Challenges for HIV vaccine dissemination and clinical trial recruitment: if we build it, will they come?

HIV vaccine availability does not guarantee uptake. Given suboptimal uptake of highly efficacious and already accessible vaccines in the United States, low vaccine coverage in the developing world, and the expectation that initial HIV vaccines will be only partially efficacious, the public health community will face formidable challenges in disseminating U.S. Food and Drug Administration (FDA)-approved HIV vaccines. HIV/AIDS stigma, fear of vaccine- induced HIV infection, social side effects of testing HIV-positive, and mistrust of government and research present additional obstacles to HIV vaccine dissemination. Increased risk behaviors because of HIV vaccine availability can undermine the effectiveness of partially efficacious vaccines in reducing HIV incidence. HIV vaccine efficacy trials also face significant challenges in recruitment of sufficient volunteers and possible increases in risk behaviors due to trial participation. Planning and designing interventions to facilitate successful recruitment for large-scale phase 3 efficacy trials is a vital step towards U.S. FDA-approved HIV vaccines. Rather than despair in the face of momentous HIV vaccine dissemination challenges, or presume unrealistically that vaccine uptake will ensue automatically and that risk behavior increases will not occur, let us deem the estimated 10-year window to an approved HIV vaccine as an opportunity to investigate and confront these challenges. A consumer research agenda founded on social marketing principles is needed to facilitate the design of empirically-based interventions tailored to the unique needs and preferences of specific segments of consumers. Social marketing interventions may increase future HIV vaccine uptake and clinical trial participation, and mitigate increases in HIV risk behaviors.     

Prospects for new TB vaccines: Stop TB Working Group on TB Vaccine Development.

Research towards the development of improved TB vaccines has reached an important turning point. A large number of vaccine candidates such as modified BCG, attenuated Mycobacterium tuberculosis and protein or DNA subunit vaccines, resulting from over a decade of work in experimental laboratory models, are now getting ready for clinical testing. The transition from laboratory to clinical trials has a wide range of strategic and technical implications. Facilities and funding need to be identified for the production of clinical vaccine lots, an issue that is difficult to tackle due to the live organisms in some of the new vaccine candidates; regulatory hurdles need to be overcome; protocols and trial sites need to be developed, for phase III clinical efficacy trials in particular. The Stop TB Working Group on TB Vaccine Development provides a global forum that brings laboratory and clinical researchers together with experts in tuberculosis control and representatives from commercial and non-profit funding agencies to address these issues and to facilitate progress towards the common goal of improved vaccination strategies for tuberculosis.     

When research becomes practice: the concept of the therapeutic misconception and challenges to consent in clinical trials

Many factors influence patients' decisions to participate in clinical trials. For many, the primary motivation is the possibility that they might derive some benefit from participation. This is particularly true for patients with limited treatment options, such as patients with advanced cancer. While this is not surprising, it is potentially problematic if patients fail to recognise the distinction between research and clinical care (a phenomenon known as the ‘therapeutic misconception’). This is becoming increasingly problematic as clinical trial designs become more complex, as clinical trials become more embedded in routine clinical care, and as trials are increasingly used by patients and clinicians to access new diagnostic platforms and therapies. We outline some of these recent trends, focusing on the cancer clinical trials landscape as this provides a good case study of the phenomenon. We conclude by making preliminary suggestions that changes to the consent process, perhaps using ‘dynamic consent’ platforms, might help to mitigate the therapeutic misconception and note the need for further research to guide strategies for improving communication and decision-making.     

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The majority of clinical trials currently and historically do not include older adults or non-white participants. While more women are being recruited, their numbers are still limited. It is very hard to interpret trial results and apply them to older adults when their participation in clinical trials is limited. The focus of this article is the lack of clinical trial participation by persons of diverse races and ethnicities and the presentation of a model infrastructure grounded in community engagement that is proving to be effective in increasing the interest and participation of older African Americans in research.     

Concise review of machine perfusion in liver transplantation

With the advances and clinical growth in liver transplantation over the last four decades the focus on expanding deceased donor organs has been in need of scientific research. In the past ten years several researchers have looked at the domain of machine perfusion as it applies to deceased donor livers. The following review focuses on the clinical trials and recent advances that will likely have the earliest entrance into the clinical arena.     

Network meta-analysis for comparing treatment effects of multiple interventions: an introduction

Systematic reviews and meta-analyses of randomized trials have long been important synthesis tools for guiding evidence-based medicine. More recently, network meta-analyses, an extension of traditional meta-analyses enabling the comparison of multiple interventions, use new statistical methods to incorporate clinical evidence from both direct and indirect treatment comparisons in a network of treatments and associated trials. There is a need to provide education to ensure that core methodological considerations underlying network meta-analyses are well understood by readers and researchers to maximize their ability to appropriately interpret findings and appraise validity. Network meta-analyses are highly informative for assessing the comparative effects of multiple competing interventions in clinical practice and are a valuable tool for health technology assessment and comparative effectiveness research.     

Almanac 2012, cell therapy in cardiovascular disease: The national society journals present selected research that has driven recent advances in clinical cardiology

The rapid translation from bench to bedside that has been seen in the application of regenerative medicine to cardiology has led to exciting new advances in our understanding of some of the fundamental mechanisms related to human biology. The first generation of cells used in phase I–II trials (mainly bone marrow mononuclear cells) are now entering phase III clinical trials with the goal of producing a cell based therapeutics that can change the outcome of cardiac disease. First generation cell therapy appears to have addressed safety concerns as well as showing ‘activity’ in numerous published meta-analyses. With the knowledge gained to date, the field is moving towards the next generation of cells—the ‘engineered’ cell—that has been developed to display a phenotype that will further enhance the myocardial repair/salvage process. This almanac review covers the latest basic research that may soon have application to humans as well as the results of the latest clinical trials.     

Sex Disparities in Cardiovascular Device Evaluations: Strategies for Recruitment and Retention of Female Patients in Clinical Device Trials

Women have historically been underrepresented in clinical trials evaluating cardiovascular devices. Existing initiatives through government agencies have made some progress, but contemporary rates of female clinical trial participation leave much room for improvement. This position paper provides a narrative review and investigates reasons for the underrepresentation of women in cardiovascular trials. The observed differences in safety and/or effectiveness of devices in women warrant a campaign to increase their trial participation with the aim of better understanding and improving outcomes. The authors propose a multifaceted approach to increasing female enrollment through the development of a national public awareness and education campaign aimed to inform women, clinician-providers, and clinical research personnel of these differences. Finally, the authors visit some barriers relevant to women and recommend ways to facilitate their participation in clinical trials through multistakeholder engagement.     

Opportunities for gene therapy in preventing vein graft failure after coronary artery bypass surgery

The poor patency rates for coronary artery bypass grafting (CABG) using autologous saphenous vein necessitate the need for continued research into the potential clinical utility of gene therapy. Bypass grafting is ideally suited for gene therapy, as graft can be genetically modified ex vivo prior to grafting in the coronary vasculature. Research to date has demonstrated effective blockade of late vein graft failure through overexpression of a variety of transgenes that modulate the proliferative, migratory and/or apoptotic indexes of cells in the graft wall. This has resulted in a substantial wealth of preclinical data that support advancement to clinical trials. Future translation into clinical trials will ensure that this exciting and highly relevant area of gene therapy is fully evaluated for potential routine clinical practice to improve patency rates of bypass graft procedures involving saphenous vein.     

Training the Workforce to Conduct Embedded Pragmatic Clinical Trials to Improve Care for People Living with Dementia and Their Caregivers

The National Institute on Aging IM bedded P ragmatic A lzheimer's Disease and Alzheimer's Disease–Related Dementias C linical T rials (IMPACT) Collaboratory serves as a national resource for the conduct of embedded pragmatic clinical trials to improve the care of people living with dementia (PLWD) in partnership with the healthcare systems that serve them. Inherent in this objective is the need to train and support a cadre of investigators prepared to conduct this work now and in the future. The Training Core of the IMPACT Collaboratory supports the training of investigators to become experts in this field through three objectives: (1) curricula development and dissemination; (2) network generation and navigation; and (3) a career development award program. The innovative approach of the Training Core will require developing content and providing training experiences that recognize the unique challenges of research at the intersection of health systems, pragmatic trials, and PLWD and their caregivers. Ultimately, we seek to build the nation's capacity to conduct research that bridges the gaps between efficacy studies to effectiveness research to implementation science. Although foundational resources in the methods of each of these areas are already available, few actually focus on pragmatic trials embedded within healthcare systems that focus on PLWD. To bring new interventions for PLWD from efficacy to widespread implementation, researchers must build diffusability, adaptability, heterogeneity, and scalability into the design of the intervention. In achieving these objectives, the Training Core will utilize the network of investigators, institutions, and stakeholders represented in the IMPACT Collaboratory. J Am Geriatr Soc 68:S21–S27, 2020 .