Ethical and practical challenges in implementing informed consent in HIV/AIDS clinical trials in developing or resource-limited countries

Background/rationale: Ethical issues regarding HIV/AIDS human research in the developing world remain under continuous evaluation; a critical area of concern includes informed consent. This paper reviews several of the most important ethical and practical aspects of informed consent in HIV research in developing countries. Enhancement of overall understanding of such key issues might promote higher ethical standards of future research. Objectives: The major objective was to address informed consent in human research in non-Western societies, and specifically in HIV clinical trials of affected adults. Secondary end-points included the consent complexities in HIV research involving vulnerable patient populations in resource-limited nations, such as children, adolescents and women. Methods: A systematic review of the published literature using MEDLINE and EMBASE from 1998 until December 2008 was performed, using the search terms ‘HIV/AIDS’, ‘informed consent’, ‘clinical trials’, ‘developing world’. Results: Ethical complexities such as participants' diminished autonomy, coercion or monetary inducement, language difficulties, illiteracy or lack of true understanding of the entire study, cultural barriers mainly due to communitarianism and social diversities were identified in the 44 studies reviewed. Informed consent of vulnerable patient populations must be tailored to their sex and developmental age, while counselling is fundamental. Children and adolescents' assent must be ensured. Local language is to be used, while trusted community leaders and local cultural representatives may convey information. Discussion: Despite the heterogeneity of studies, similarities were identified. Providing adequate and comprehensive information and assessing the true understanding of the research represent fundamental prerequisites. Potential solutions to the critical areas of concern include peer counselling and meetings with local community leaders or local cultural representatives. Conclusions: International investigators of HIV human research should bear in mind these ethical issues and their potential solutions, when trying to ensure ethical research conduct, based on a truly informed and culturally relevant consent.     

Ethical issues concerning therapeutic studies in inflammatory bowel disease

Physicians often take on responsibilities beyond medical care regarding their patients with ulcerative colitis and Crohn's disease: they serve as the patients' advocates to nonmedical entities and individuals, including insurance companies, schools, employers, companions, and family members. These responsibilities create a more complex relationship between the patient and their IBD physician. In addition, these responsibilities may accentuate ethical issues for the physician who is also engaged in clinical treatment trials for inflammatory bowel disease (IBD). Ethical issues include therapeutic misconception, clinical equipoise, and financial and nonfinancial conflicts of interest. Physicians who refer patients with IBD to enroll in treatment trials, as well as clinician investigators who conduct studies should consider measures to clarify the separation between clinical care and participation in a therapeutic study, and to ensure the ethical treatment of patients. These precautionary measures may include payment of participants to emphasize that the research study is different from clinical care, consent by an investigator other than the treating physician, and care to disclose conflicts of interest to the patient and the medical community in presentations and publications. If the financial conflict is too great, a physician should not participate in the clinical trial.     

Patient resources in the therapeutic education of haemophiliacs in France: their skills and roles as defined by consensus of a working group

Summary. The activities of ‘expert patients’ or ‘patient tutors’, who help educate their peers, are gaining recognition in the health care system. This study investigates the role played by such patients in therapeutic education programmes organized by caregivers to validate the role of patients in implementing the therapeutic education of haemophilic patients and to define the skills required for such activities. This study employs the consensus methodology recommended by France’s National Authority for Health. The working group includes seven caregivers from Hemophiliac Treatment Centers (HTCs) and three patients from the French Association of Hemophiliacs (FAH). The role of patients in haemophilia education is recognized. Patients participating in the education of their peers are referred to as ‘patient resources’. A patient resource should be an adult, a volunteer and live in the same region as his peers. Candidates are chosen by the FAH and the HTCs to serve based on their motivation to facilitate the education of other patients as well as on their psychological and pedagogical aptitudes. A patient resource participates in the conception and administration of therapeutic education programmes. He also mediates between the caregivers and the patients. He ensures that the patients understand the material and are able to apply their knowledge in daily life. His activities are governed by professional ethics. Seven categories of skills were defined, permitting the group to determine precisely which skills are required to function as a patient resource. Supervision of the patients is planned to reinforce reflexive practices in the patients. Evolution of the health care system has led patients to become involved in therapeutic education. This phenomenon calls for a framework to be developed and an evaluation of its eventual effects.     

What is a cure and how do we get there?

Summary.  The absence of adequate treatment for most of the world's 400 000 individuals with haemophilia makes the development of a cure compelling. Advances in the basic molecular sciences over the past 20 years have resulted in the feasibility of curing haemophilia through the application of gene therapy. However, the reality of this therapeutic strategy is highly complex. In addition, challenges to achieving a cure exist beyond the basic scientific hurdles. Thoughtful attention must also be given to a number of interrelated issues, including ethical considerations in patient recruitment, informed consent and geographical variables of global clinical trials. The global inequalities in healthcare mean that the ethics of international medical research, especially when it includes countries where people usually do not receive quality care, become much more complicated. The majority of haemophiliacs lives in developing countries and is a valuable resource of human subjects who could be enrolled in clinical trials. When recruiting subjects globally, investigators must be ever mindful that the patient population is a precious resource, which must be treated with respect and care. This presents a major challenge for investigators engaged in trials of haemophilia gene therapy to ensure that the informed consent process is current and comprehensive, that therapeutic misconceptions are appropriately managed, and that the roles of the researcher and physician are clear. Global clinical gene-therapy trials are an important and appropriate component in the quest to achieve a cure for haemophilia. When trials follow identical internationally accepted standards, a successful outcome can be achieved for trials including developing countries, if country specific cultural and economic aspects are considered.     

Setting up a respiratory trials unit

Clinical trials are essential in advancing our knowledge and treatment of patients with respiratory disease. Conducting well-designed clinical studies which accurately and reliably answer important clinical questions is challenging. The expertise required to deliver such studies is increasingly concentrated in clinical trials units. This article will describe some of the challenges associated with clinical studies and the methods and personnel involved in a clinical trials unit.     

Public attitudes towards research participation during an infectious disease pandemic: a qualitative study across four European countries

BackgroundPandemics of infectious disease are recurrent events that impact global health and security. International, collaborative planning for future pandemics is a priority for public health officials, the research community, and the general public. However, little is known about the public's attitudes to participating in pandemic research and about their views on associated ethical dilemmas. We aimed to determine public perceptions about involvement in clinical research conducted in primary and critical care during a pandemic.MethodsWe conducted ten, 2 hour focus groups (6–10 participants each) and 16 one-to-one follow-up interviews involving 80 members of the public in Belgium, Poland, Spain, and the UK between Sept 1 and Dec 31, 2015. Recruitment was through local advertisement. Data were collected by local researchers who followed a scenario-based topic guide, transcribed verbatim and translated into English. We used framework analysis to identify the range and diversity of participants' perspectives.FindingsPublic understandings of pandemics were shaped by personal factors (illness during the H1N1 pandemic, experience of life-threatening illness) and social factors (historical references, media, public health information). Motivations to participate in pandemic research were influenced by altruism, therapeutic misconception, trust, and perception of risk. Use of routinely collected data and clinical samples without explicit prior consent was supported in principle, but was less acceptable when a profit motive was perceived. Participants recognised and appreciated the protections provided by ethically robust research procedures. However, they described having become desensitised to the importance and meaning of consent processes because of the frequency with which they authorise terms and conditions in everyday life. Participants proposed different models that might apply in a pandemic context (eg, advanced consent, verbal consent).InterpretationPublic engagement in clinical research on pandemic planning is possible, useful, but as yet underdeveloped in Europe. Effective pandemic preparation for clinical research requires active public engagement to mitigate therapeutic misconception and engender trust. This bottom-up approach to ascertaining public views on pandemic research participation has identified support for minimising disproportionate research protection procedures for publicly funded, low risk studies.FundingEuropean Union Seventh Framework Programme under the project Platform foR European Preparedness Against (Re-)emerging Epidemics (PREPARE) (grant agreement 602525).     

Management of digestive cancers during the COVID-19 second wave: A French intergroup point of view (SNFGE,FFCD, GERCOR,UNICANCER, SFCD,SFED, SFRO,ACHBT, SFR)

IntroductionThe COVID-19 pandemic has major impact of healthcare systems, including cancer care pathways. The aim of this work is to discuss in a multidisciplinary approach the therapeutic and/or strategies adaptations for patients treated for a digestive cancer during the European second wave of COVID-19 pandemic.MethodsA collaborative work was performed by several French societies to answer how to preserve digestive cancer care with no loss of chance during the second wave of COVID-19. In this context, all recommendations are graded as expert’s agreement according to level evidence found in literature until October 2020 and the experience of the first wave of the COVID-19 pandemic.ResultsAs far as possible, no therapeutic modification should be carried out. If necessary, therapeutic adjustments may be considered if they do not constitute a loss of chance for patients. Considering the level of evidence all therapeutic modifications need to be discussed in multidisciplinary tumor board meeting and with patient consent. By contrast to first wave cancer prevention, cancer screening, supportive care and clinical trials should be continued.ConclusionRecommendations proposed could limit cancer excess mortality due to the COVID-19 pandemic but should be adapted according to the situation in each hospital.     

Leave me out: Patients’ characteristics and reasons for opting out of a pragmatic clinical trial involving medication adherence

Opt-out procedures are sometimes used instead of standard consent practices to enable patients to exercise their autonomous preferences regarding research participation while reducing patient and researcher burden. However, little is known about the characteristics of patients who opt-out of research and their reasons for doing so. We gathered such information in a large pragmatic clinical trial (PCT) evaluating the effect of theory informed text messages on medication adherence.Eligible patients, identified through electronic health records, were sent information about the study and provided with an opportunity to opt-out. Those opting out were asked to complete a voluntary survey regarding their reasons for doing so. Demographic data were compared among patients opting-out vs those included in the study using chi-squared tests and a log binomial regression model.Of 9046 patients receiving study packets, 906 (10.0%) patients returned opt-out forms. Of those, 451 (49.8%) returned the opt-out survey. Patients who opted out were more likely to be older, white, and nonHispanic than those who were included in the PCT. Survey respondents expressed high levels of trust in their health care providers, research, and system. Nearly half (46.6%) reported concerns about time as a reason to opt-out.In this PCT, 10% of patients receiving packets opted out, with significant differences in age, race, gender, and ethnicity compared to those included. Future trials should further investigate representativeness and reasons patients choose to opt-out of participating in research.     

LDL cholesterol: How low to go?

Epidemiology and the results of large-scale outcome trials indicate that the association of LDL with atherosclerotic cardiovascular disease is causal, and continuous not only across levels seen in the general population but also down to sub-physiological values. There is no scientific basis, therefore, to set a target or ‘floor’ for LDL cholesterol lowering, and this presents a clinical and conceptual dilemma for prescribers, patients, and payers. With the advent of powerful agents such as proprotein convertase/subtilisin kexin type 9 (PCSK9) inhibitors, LDL cholesterol can be lowered profoundly but health economic constraints mandate that this therapeutic approach needs to be selective. Based on the need to maximize the absolute risk reduction when prescribing combination lipid-lowering therapy, it is appropriate to prioritize patients with the highest risk (aggressive and established CVD) who will obtain the highest benefit, that is, those with elevated LDL cholesterol on optimized statin therapy.     

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.     

Cost Evaluation of Rhythm Control Methods for Atrial Fibrillation: Evidence from CTAF

Atrial fibrillation (AF) is a highly prevalent arrhythmia that is difficult to treat and generates important health care costs. One consideration in the selection of various therapeutic options is the cost of a given treatment compared to that of alternatives. The Canadian Trial of Atrial Fibrillation (CTAF) evaluated the effectiveness of sinus rhythm maintenance with amiodarone compared to propafenone or sotalol in a prospective, randomized fashion. A subsequent CTAF substudy of the medical costs associated with amiodarone vs. propafenone/sotalol found that amiodarone decreased AF-related costs. This paper reviews the results of the CTAF cost-analysis substudy in the context of other analyses in the literature of the cost effectiveness of amiodarone in AF. The costs associated with amiodarone therapy are no greater than for other sinus rhythm maintenance drugs, and for some cost categories and some patient subgroups are likely to be less, despite amiodarone's greater therapeutic efficacy. However, additional considerations are important in evaluating the clinical place of amiodarone, including its adverse effect and pharmacokinetic profile. As well, the results of recent randomized clinical trials have highlighted the limitations of sinus rhythm maintenance as a primary therapeutic objective in AF. The decision about whether and at what point to use amiodarone in a given patient requires a careful analysis of the individual case, in terms of symptomatology during AF, the response to previous treatment regimes, and risk factors for various forms of adverse drug reactions.     

Increasing underrepresentation of elderly patients with advanced colorectal or non-small-cell lung cancer in chemotherapy trials

Background: Elderly patients are underrepresented in chemotherapy trials for advanced colorectal cancer (CRC) and non‐small‐cell lung cancer (NSCLC). However, the change in underrepresentation over time has not been documented. Aims: This study aimed to quantify (i) the change in the median age of patients enrolled in clinical trials for metastatic CRC and NSCLC between 1982–1991 and 1992–2001 compared with the general colorectal and lung cancer population, and (ii) the proportion of trials with an upper age limit for eligibility. Methods: A retrospective review of data from the Victorian Cancer Registry and all large published randomized chemotherapy trials for advanced CRC and NSCLC between 1982 and 2001 was conducted. Results: The median age of patients with CRC enrolled in clinical trials remained constant between the two decades (62.0 and 62.2 years), whereas the median age of the CRC population increased from 68.4 to 70.2 years, increasing the median age difference from 6.4 to 8.0 years. The median age of patients with lung cancer in clinical trials increased from 59.8 to 61.8 years, whereas the median age of the lung cancer population increased from 67.4 to 70.4 years, widening the age difference from 7.6 to 8.6 years. More trials set an upper age limit for eligibility in the first decade than in the second decade for both CRC (51 vs 29%, P = 0.04) and NSCLC (68 vs 41%, P = 0.03). Conclusion: International clinical trials for CRC and NSCLC are becoming increasingly unsuitable for application to Australian patients because of the increasing age discrepancy, despite fewer trials restricting eligibility by age.     

Evaluating glucose-lowering treatment in older people with diabetes: Lessons from the IMPERIUM trial

Understanding the benefits and risks of treatments to be used by older individuals (≥65 years old) is critical for informed therapeutic decisions. Glucose-lowering therapy for older patients with diabetes should be tailored to suit their clinical condition, comorbidities and impaired functional status, including varying degrees of frailty. However, despite the rapidly growing population of older adults with diabetes, there are few dedicated clinical trials evaluating glucose-lowering treatment in older people. Conducting clinical trials in the older population poses multiple significant challenges. Despite the general agreement that individualizing treatment goals and avoiding hypoglycaemia is paramount for the therapy of older people with diabetes, there are conflicting perspectives on specific glycaemic targets that should be adopted and on use of specific drugs and treatment strategies. Assessment of functional status, frailty and comorbidities is not routinely performed in diabetes trials, contributing to insufficient characterization of older study participants. Moreover, significant operational barriers and problems make successful enrolment and completion of such studies difficult. In this review paper, we summarize the current guidelines and literature on conducting such trials, as well as the learnings from our own clinical trial (IMPERIUM) that assessed different glucose-lowering strategies in older people with type 2 diabetes. We discuss the importance of strategies to improve study design, enrolment and attrition. Apart from summarizing some practical advice to facilitate the successful conduct of studies, we highlight key gaps and needs that warrant further research.     

Medical ethics in the 21st century

OBJECTIVES: To foresee how medical ethics may develop in the 21st century. DESIGN: We have looked into our crystal ball to see what factors are likely to drive medical ethics over the next few decades. We have given examples of how such factors might affect specific issues. RESULTS: Those factors that we identified as likely to shape the future of medical ethics are: Globalization: Medical ethics is likely to have to grapple increasingly with ethical issues arising from the huge discrepancies in the level of health care available in different countries. Increase in longevity: We predict that there will be, at least amongst the richer nations, a significant increase in life expectancy. This will result in issues of resource allocation becoming increasingly problematic within medicine. Child enhancement: Developments in genetics combined with control of reproduction will make it possible to select our children for a broad range of characteristics. There are optimistic and pessimistic predictions as to how such power will be used. In either case, this area will be an important focus of concern in medical ethics. The biological determination of behaviour: Genetic research will lead to an increasing sense that undesirable behaviour is genetically determined. This will lead to a re-examination of such concepts as criminal responsibility. Therapeutic research and clinical practice: We predict that an increasing amount of clinical practice will be within the setting of clinical trials. The ethics of therapeutic research and clinical practice will need to be brought within a coherent framework.     

A coverage plan for health centres in Murewa District in Zimbabwe: an example of action research

Good access to health facilities providing good first-level health care remains problematic in many developing countries. It is a hindrance to effective and efficient functioning of the hospital, as outpatient departments become overcrowded with patients from areas without health centres. In many cases the quality of care delivered to these patients is poor because within the district health system the hospital is not the best place for the supply of comprehensive, integrated and continuous care. Eventually, high hospital involvement in first-level care can jeopardize the delivery of adequate referral care for those patients who desperately need the hospital's technology and expertise. This paper provides an account of the way this problem was investigated and managed by the district health management team in the Murewa district in north-east Zimbabwe. The design of a comprehensive ‘master plan’ or ‘coverage plan’ is presented as well as the problems and difficulties encountered. The Murewa experience highlights the relevance of a coverage plan for rational and coherent health infrastructure planning at district level. The approach followed by the Murewa team illustrates the use of action research as an integral part of the management of district health systems.     

Plant-produced idiotype vaccines for the treatment of non-Hodgkin's lymphoma: safety and immunogenicity in a phase I clinical study

Plant-made vaccines have been the subject of intense interest because they can be produced economically in large scale without the use of animal-derived components. Plant-made therapeutic vaccines against challenging chronic diseases, such as cancer, have received little research attention, and no previous human clinical trials have been conducted in this vaccine category. We document the feasibility of using a plant viral expression system to produce personalized (patient-specific) recombinant idiotype vaccines against follicular B cell lymphoma and the results of administering these vaccines to lymphoma patients in a phase I safety and immunogenicity clinical trial. The system allowed rapid production and recovery of idiotypic single-chain antibodies (scFv) derived from each patient's tumor and immunization of patients with their own individual therapeutic antigen. Both low and high doses of vaccines, administered alone or co-administered with the adjuvant GM-CSF, were well tolerated with no serious adverse events. A majority (>70%) of the patients developed cellular or humoral immune responses, and 47% of the patients developed antigen-specific responses. Because 15 of 16 vaccines were glycosylated in plants, this study also shows that variation in patterns of antigen glycosylation do not impair the immunogenicity or affect the safety of the vaccines. Collectively, these findings support the conclusion that plant-produced idiotype vaccines are feasible to produce, safe to administer, and a viable option for idiotype-specific immune therapy in follicular lymphoma patients.     

Stakeholder acceptability of adolescent participation in clinical trials for biomedical HIV prevention products: considerations from Tanzania and India

Researchers and advocates have increasingly called for adolescent participation in clinical trials for new HIV prevention products, particularly adolescent girls in areas most affected by the epidemic. However, recent trials have highlighted the challenges for young women and adolescents to be able to effectively use new products that require daily dosing. This analysis provides a highly relevant context for this challenging environment by examining community members acceptability of adolescent girls’ participation in clinical trials for new HIV prevention products. We conducted 41 in-depth interviews in Dar es Salaam, Tanzania and Pune, India with 22 key informants (KIs). Cultural perspectives on adolescent sexuality varied between countries, with KIs in Tanzania more readily acknowledging adolescent girls’ sexual activity than KIs in India. KIs in both countries felt strongly adolescents must be well-informed about research concepts prior to participation, and emphasis should be given to preventative misconception. Despite concern in both countries that the trials might be seen as encouraging sexual behavior, KIs in Tanzania overwhelmingly supported adolescent inclusion, whereas KIs in India were more cautious. Involving adolescent girls in clinical trials for new HIV prevention products is potentially acceptable, although meaningful community engagement will be necessary.     

Barriers to informed consent in clinical trials

Clinical trials are a type of scientific study conducted in human beings. They are designed to evaluate the safety and effectiveness of new drugs, procedures, or other means of treating, diagnosing, or preventing diseases. The ethical issues involved in clinical trials are nothing new, but because of the increased access to studies, they are steadily affecting more people. The sheer volume of clinical trials, as well as the number of patients and professionals involved in them, has increased in the past decade. Informed consent is a key element of clinical research. Meaningful informed consent requires that subjects weight the associated risks and benefits of an experimental intervention and then voluntarily give consent. One concern regarding informed consent in research is the confusion between therapeutic intervention and experimental treatment. This confusion could lead to barriers in informed consent. This column addresses this concern and includes a case study to illustrate the misunderstandings that might arise from the patient who is compelled to consent to clinical trials because of his sense of hopelessness from a chronic health condition and the traditional medical intervention he is receiving.