Ethical and legal constraints to children's participation in research in Zimbabwe: experiences from the multicenter pediatric HIV ARROW trial

ABSTRACT: BACKGROUND: Clinical trials involving children previously considered unethical are now considered a necessity because of the inherent physiological differences between children and adults. An integral part of research ethics is the informed consent, which for children is obtained by proxy from a consenting parent or guardian. The informed consent process is governed by international ethical codes that are interpreted in accordance with local laws and procedures raising the importance of contextualizing their implementation. DISCUSSION: The Zimbabwean parental informed consent document for children participating in clinical research is modeled along western laws of ethics and requires that the parent or legally authorized representative provide consent on behalf of a minor. This article highlights the experiences and lessons learnt by Zimbabwean researchers in interpreting and obtaining informed consent for orphaned children participating in a collaborative HIV clinical trial involving the Medical Research Council, United Kingdom and four centers, three of which are in Uganda. Researchers were faced with a situation where caregivers of orphaned children were not permitted to provide informed consent for trial participation if the Zimbabwean courts had not legally appointed them. The situation contrasted with general clinical practice where legal papers where not required for providing consent for surgical procedures for example. SUMMARY: Experiences gained from this clinical trial revealed that while there may be internationally established guidelines governing the process of obtaining informed consent for children participating in research, there may be need to be cognizant of the culture within which the research is taking place. This may call for the development of an ethico-legal framework that governs research-involving children in Zimbabwe that would facilitate their participation in clinical research, while ensuring that they are protected from exploitation. The Medical Research Council of Zimbabwe has since started developing that framework in a process that is expected to involve critical stakeholders namely the community including children, ethicists, the legal fraternity and researchers.     

Experts' opinions on ethical issues of genetic research into Alzheimer's disease: results of a Delphi study in the Netherlands

van der Vorm A, van der Laan AL, Borm G, Vernooij‐Dassen M, Rikkert MO, van Leeuwen E, Dekkers W. Experts' opinions on ethical issues of genetic research into Alzheimer's disease: results of a Delphi study in the Netherlands. Most publications on the ethical aspects of genetic research into Alzheimer's Disease (AD) concentrate on the differences between the opinions of professionals and non‐professionals. Differences in rating of morally relevant issues between groups of professionals have not yet been described. A modified Delphi study in two rounds was held to identify differences between groups of experts (i.e. clinicians, representatives of patient organisations, ethicists and persons with a commercial background). The strongest correlation was found between the opinions of ethicists and representatives of patient organisations (0.67) and between clinicians and ethicists (0.62). Moderate correlation (0.55) was found between the opinions of clinicians and representatives of patient organisations. Persons with a commercial background showed a weak correlation with clinicians (0.41), ethicists (0.35) and representatives of patient organisations (0.30). These differences in rating of morally relevant issues between various professional groups are relevant for clinical practice and dementia care, particularly the different rating of prenatal diagnosis found between clinicians and representatives of patient organisations. Interdisciplinary consultations between various professional groups –including at least researchers, clinicians and ethicists –are recommended to guarantee that all considerations will be incorporated into the debate on ethical issues of genetic research into AD.     

The SickKids Genome Clinic: developing and evaluating a pediatric model for individualized genomic medicine

Our increasing knowledge of how genomic variants affect human health and the falling costs of whole‐genome sequencing are driving the development of individualized genomic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to anticipate, diagnose and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific and clinical paradigms. The potential benefits of pre‐symptomatic identification of at‐risk individuals, improved diagnostics, individualized therapy, accurate prognosis and avoidance of adverse drug reactions coexist with the potential risks of uninterpretable results, psychological harm, outmoded counseling models and increased health care costs. Here we review the challenges, opportunities and limits of integrating genomic analysis into pediatric clinical practice and describe a model for implementing individualized genomic medicine. Our multidisciplinary team of bioinformaticians, health economists, health services and policy researchers, ethicists, geneticists, genetic counselors and clinicians has designed a ‘Genome Clinic’ research project that addresses multiple challenges in pediatric genomic medicine – ranging from development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference and the ethics of consent.     

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the 'Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research.     

Exploring the ethics of global health research priority-setting

Background

Thus far, little work in bioethics has specifically focused on global health research priority-setting. Yet features of global health research priority-setting raise ethical considerations and concerns related to health justice. For example, such processes are often exclusively disease-driven, meaning they rely heavily on burden of disease considerations. They, therefore, tend to undervalue non-biomedical research topics, which have been identified as essential to helping reduce health disparities. In recognition of these ethical concerns and the limited scholarship and dialogue addressing them, we convened an international workshop in September 2015. The workshop aimed to initiate discussion on the appropriate relationship between global and national levels of health research priority-setting and to begin exploring what might be ethically required for priority-setting at each of those levels.

Main text

This paper comprises our reflections following the workshop. Its main objective is to launch a research agenda for the ethics of global health research priority-setting. We identify three domains of global health research priority-setting—scope, underlying values and substantive requirements, and procedural considerations. For each domain, specific research questions are highlighted and why they need to be explored is explained. Some preliminary thoughts and normative arguments as to how the research questions might be answered are also offered. For example, we provide initial ideas about the appropriate relationship between different priority-setting levels and what values and substantive considerations should guide or underpin global health research priority-setting as a matter of justice.

Conclusion

We anticipate that framing a new research agenda for the ethics of global health research priority-setting will spur ethicists, researchers, and policymakers to refocus their efforts on developing more rigorous and ethically sound approaches to priority-setting.

     

When research seems like clinical care: a qualitative study of the communication of individual cancer genetic research results

Background  

Research ethicists have recently declared a new ethical imperative: that researchers should communicate the results of research to participants. For some analysts, the obligation is restricted to the communication of the general findings or conclusions of the study. However, other analysts extend the obligation to the disclosure of individual research results, especially where these results are perceived to have clinical relevance. Several scholars have advanced cogent critiques of the putative obligation to disclose individual research results. They question whether ethical goals are served by disclosure or violated by non-disclosure, and whether the communication of research results respects ethically salient differences between research practices and clinical care. Empirical data on these questions are limited. Available evidence suggests, on the one hand, growing support for disclosure, and on the other, the potential for significant harm.     

Research ethical challenges in cross-disciplinary and cross-cultural health research: the diversity of codes

The scope of health research has increased considerably during the last three to four decades, both geographically and regarding the range of disciplines participating in biomedical research. In other words cross-cultural and cross-disciplinary projects are much more common in the World's biomedical research of today. For the large part that involves human research subjects, ethics based on fundamental human values is still an integrated part of project planning and management. However, in the light of the increasing complexity of research, the controlling codes (i.e. laws, declarations, conventions and guidelines) have undergone important changes and have increased considerably in numbers. Hence, groups from different disciplines and cultures need to adjust their projects' research ethical policies and implementations in accordance with the various codes' common denominators. Sometimes research ethical codes are even incompatible at certain points. The article describes key ethical aspects of cross-cultural and cross-disciplinary projects, with special emphasis on acquiring consent, avoiding harm, attending to needs, and describing the obligations when a project is over. On this background the authors conclude that researchers in the planning phase of a project should: 1) seek knowledge and professional advice related to the transgression of cultural and disciplinary borders, 2) introduce a long-term perspective for a project's activities and consequences, and 3) select the appropriate among the existing many ethical codes. These suggestions apply to several stakeholders: researchers, scientific societies, agencies for scientific support, information and ethical control, as well as research political agencies.     

Ethical and legal constraints to children’s participation in research in Zimbabwe: experiences from the multicenter pediatric HIV ARROW trial

Background

Clinical trials involving children previously considered unethical are now considered essential because of the inherent physiological differences between children and adults. An integral part of research ethics is the informed consent, which for children is obtained by proxy from a consenting parent or guardian. The informed consent process is governed by international ethical codes that are interpreted in accordance with local laws and procedures raising the importance of contextualizing their implementation.

Findings

In Zimbabwe the parental informed consent document for children participating in clinical research is modeled along western laws of ethics and requires that the parent or legally authorized representative provide consent on behalf of a minor. This article highlights the experiences and lessons learnt by Zimbabwean researchers in obtaining informed consent from guardians of orphaned children participating in a collaborative HIV clinical trial involving the Medical Research Council, United Kingdom and four centers, three of which are in Uganda. Researchers were faced with a situation where caregivers of orphaned children were not permitted to provide informed consent for trial participation. The situation contrasted with general clinical practice where consent for procedures on orphans is obtained from their caregivers who are not legal guardians.

Conclusion

The challenges faced in obtaining informed consent for orphans in this clinical trial underscores the need for the Zimbabwe ethics committee to develop an ethical and legal framework for pediatric research that is based on international guidelines while taking into account the cultural context. The Medical Research Council of Zimbabwe has since started the process that is expected to involve critical stakeholders namely the community including children, ethicists, the legal fraternity and researchers.     

Commentary: the relative research unit: providing incentives for clinician participation in research activities

Recent nationwide initiatives to accelerate clinical and translational research, including comparative effectiveness research, will increasingly require clinician participation in research-related activities at the point-of-care, activities such as participant recruitment for clinical research studies and systematic data collection. A key element to the success of such initiatives that has not yet been adequately addressed is how to provide incentives to clinicians for the time and effort that such participation will require. Models to calculate the value of clinical care services are commonly used to compensate clinicians, and similar models have been proposed to calculate and compensate researchers' efforts. However, to the authors' knowledge, no such model has been proposed for calculating the value of research-related activities performed by noninvestigator-clinicians, be they in academic or community settings. In this commentary, the authors propose a new model for doing just that. They describe how such a relative research unit model could be used to provide both direct and indirect incentives for clinician participation in research activities. Direct incentives could include financial compensation, and indirect incentives could include credit toward promotion and tenure and toward the maintenance of specialty board certification. The authors discuss the principles behind this relative research unit approach as well as ethical, funding, and other considerations to fully developing and deploying such a model, across academic environments first and then more broadly across the health care community.     

Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research

As with many new diagnostic technologies, the recent rapid emergence of array comparative genome hybridization in clinical genetics provides the power to observe new biological phenomena before their clinical significance is well understood. This raises ethical issues for clinicians when applying the technologies. However, at this early stage of research and development on array comparative genome hybridization, the ethical implications of the conduct of research, as well as how research findings are presented and interpreted, should also be considered by the research, clinical, and ethics communities. These considerations are especially important in the use of array comparative genome hybridization to study complex and common traits. We examined recent publications on autism as an example of the application of array comparative genome hybridization to a complex phenotype. Our goal was to identify points to consider for researchers, clinicians, and patients/families to ensure responsible and ethical design, presentation, and interpretation of these kinds of studies.     

Ethics and health. Challenges and reflections

In this essay, the concepts of ethics, bioethics, and professional ethics are reviewed. In addition, we analyzed the relationship between ethics and medicine, the conditions that can be source of ethical dilemmas, and the influence of ethics in the doctor-patient relationship, in the clinical work of the physician, and in an individual and institutional process of decision-making. Some factors that result from the interrelationship between ethics and health care, in particular the need for preserving and increasing the human dimension in medical practice, are discussed. Finally, the idea is supported that to achieve the purpose previously mentioned, three challenges must to be overcome: to defeat reductionism in analysis of medical matters, to accept the uncertainty of medical work and the attempt to reach adequate levels of equity in the development of health services.     

The Genome Clinic: A Multidisciplinary Approach to Assessing the Opportunities and Challenges of Integrating Genomic Analysis into Clinical Care

Our increasing knowledge of how genomic variants affect human health and the falling costs of whole‐genome sequencing are driving the development of individualized genetic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to guide health care decisions throughout life, to anticipate, diagnose, and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific, and clinical paradigms. The potential benefits of presymptomatic identification of at risk individuals, improved diagnostics, individualized therapy, accurate prognosis, and avoidance of adverse drug reactions coexist with the potential risks of uninterpretable results, psychological harm, outmoded counseling models, and increased health care costs. Here, we review the challenges of integrating genomic analysis into clinical practice and describe a prototype for implementing genetic medicine. Our multidisciplinary team of bioinformaticians, health economists, ethicists, geneticists, genetic counselors, and clinicians has designed a “Genome Clinic” research project that addresses multiple challenges in genomic medicine—ranging from the development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference, and the ethics of consent.     

Ethics of international clinical research collaboration - the experience of AlloStem

This paper examines the ethics of international clinical collaboration in stem cell research by focusing on the AlloStem project. AlloStem is an international research programme, financed by the European Union under the Sixth Framework Programme, with the aim of advancing the use of stem cells in treating leukaemia and other haematological diseases. Several areas of ethical importance are explored. Research justification and the need to consider both deontological and teleological aspects are examined. Ethical sensitivity in research and the requirement to respond to areas of ethical concern identified by the European Commission, such as the involvement of human beings, the use of human tissue, and the use of animals are also explored. Ethical issues around project structure and management, such as ethical standardization in international research, and achieving set targets are discussed. The ethical importance of dissemination of findings and teaching in clinical research is also considered. Finally, the distribution of benefits is addressed and the importance of distributive justice is emphasized.     

The Nazis, guide of the International Conference of Harmonization and ethics committees

This article begins with the basic ethical principles in clinical research. The four moral principles of autonomy, beneficence, non-maleficence, and justice are reviewed. Likewise, a historical review of the participation of German physicians and the medical establishment that carried out the policies of the Third Reich is examined, and delineates several moral failures attributable to these physicians during the dark period of history known as the Holocaust. Medical ethics were completely ignored during that period, and thus, the Nuremberg Code was enacted for regulating human research by means of informed consent. A historical vision of the universal documents for ethics in clinical research has been reviewed from the Declaration of Helsinki in 1964 to the ICH Guideline (International Conference of Harmonisation) for Good Clinical Practice (GCP) in 1996. The ICH Guideline is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve participation of human subjects. The guide was developed with consideration of the current GCP of the European Union, Japan, and the U.S. Finally, we establish the composition, functions, and operations of the Ethic Committees that ensure the rights, safety, well-being, and confidentiality statement of subjects who participate in clinical research studies and document that protection by reviewing and approving/rejecting a study protocol, and evaluate research personnel, the research site, and materials and methods used for obtaining and recording informed consent protocol from subjects participating in the study.     

Clinical and research ethics as moral strangers

This article takes issue with those who defend a brand of clinical research ethics that tends to substitute the ethics of clinical care of patients being recruited as trial subjects. The distinction between therapeutic and non-therapeutic studies is being disregarded by arguing that research is concerned with the pursuit of knowledge rather than with the medical benefits for patients. Non-competent patients may therefore be recruited for studies that will offer them no medical benefits in spite of involving them in the inherent risks of any biomedical trial. Supported by the World Medical Association, clinicians tend to shun the use of placebos in randomized trials, because of the therapeutic void created in the control group. Nevertheless, investigators continue to consider that scientific purity demands the use of placebos as the most appropriate comparator, even if risks to patient-subjects are increased. Equipoise and clinical equipoise have been suggested as adequate criteria to evaluate the need for a clinical trial, when genuine uncertainty about the equivalence of medical measures requires clarification. If equipoise is understood as a balanced situation where alternatives are equivalent and exchangeable in the view of experienced and current medical thought, no comparison seems warranted until a substantiated doubt about their true equivalence appears. Whereas respecting equipoise is an important measure to curb redundant research, new trials become mandatory if equivalence is reliably questioned. In the best interests of patients being recruited for clinical trials, they should continue to be the full beneficiaries of clinical ethics, in addition to receiving the protection of research ethics. Placebos and sub-medication for control groups are to be used sparingly, and best existing therapy should be employed as control when new and promising agents are developed.     

Residents' access to ethics consultations: knowledge, use, and perceptions.

PURPOSE: To examine residents' levels of awareness, use, and perceptions of the ethics consultation service at Loyola University Medical Center, a large Midwestern academic teaching hospital. METHOD: In 2001-2002, the authors conducted a cross-sectional survey and semistructured interviews about knowledge and use of the ethics consultation service among all 229 internal medicine, surgery, anesthesiology, pediatrics, and medicine-pediatrics residents. Chi-square and t tests were used to compare categorical and continuous variables. RESULTS: In all, 135 (59%) of the residents responded, and of these 22 (16%) completed an interview. Most survey respondents (76%) reported awareness of the ethics consultation service, although only 28 (21%) indicated they knew how to request one. Most respondents (89%) had never personally requested an ethics consultation. Thirteen residents (10%) had wanted to call an ethics consultation, but decided not to request one. Residents reported barriers to requesting an ethics consultation were the attending physician's opposition (46%), lack of awareness of the ethics consultation service (15%), and negative perceptions of ethics consultations (15%). CONCLUSION: Several barriers hindered residents' use of ethics consultation services. Health care institutions should systematically educate employees about the availability and use of ethics consultation services. Institutions should establish mechanisms to give health care professionals in subordinate roles within the medical hierarchy a safe way to access and use the service.