Informed consent from cognitively impaired persons participating in research trials: comparative law observations

This article addresses the ethical requirements to be considered when conducting clinical trials involving human subjects whose mental condition limits their ability to understand the information and to express fully autonomous and informed consent. It does not address other categories of vulnerable persons, such as children, or advanced directives concerning end-of-life care. There are many ethical issues entailed in clinical trials involving subjects with mental disabilities: how to obtain informed consent, balancing risks and benefits, balancing individual benefits with collective scientific and social interests, legal representation and many more. This article focuses on the issues surrounding the concept of minimal risk and the relationship between informed consent and risk. These issues are addressed with particular emphasis on the regulations adopted by the European Union and the federal government of the United States of America. The conclusion proposes a list of working criteria.     

Empty ethics: the problem with informed consent

Informed consent is increasingly heralded as an ethical panacea, a tool to counter autocratic and paternalistic medical practices. Debate about the implementation of informed consent is constricted and polarised, centering on the right of individuals to be fully informed and to freely choose versus an autocratic, paternalistic practice that negates individual choice. A bioethical framework, based on a principle-led form of reductive/deductive reasoning, dominates the current model of informed consent. Such a model tends to abstract the process of consent from its clinical and social setting. By flashing out the social process involved when patients and healthy volunteer subjects consent to take part in clinical drug trials, this paper attempts to address the problem arising from the current 'empty ethics' model. My arguments are substantiated by qualitative interview data drawn from a study I conducted on the process of consent as experienced by participants in clinical drug trials.     

Human experimentation in historical and ethical perspectives

Prepared as background material for a World Health Organization/Council for International Organizations of Medical Sciences document, Proposed International Guidelines for Biomedical Research Involving Human Subjects (1982), this article reviews historical aspects of human experimentation and considers several current issues. It refers to early experiments, including auto-experiments by physicians; traces the history of drug trials through the pharmacotherapeutic revolution and the thalidomide tragedy; and describes the formulation of ethical requirements during the Weimar Republic in Germany. Contemporary problems discussed are the use of controls and placebos, investigators as subjects, special categories of subjects, and informed and vicarious consent. The text of the proposed WHO/CIOMS Guidelines is appended.     

从贝尔蒙报告审视医疗器械临床试验的伦理问题

医疗器械临床试验是最直接最有效地检测医疗器械性能的方式，贝尔蒙报告是对基本的道德原则及方针的陈述，用来帮助在解决涉及人体实验对象的科研中所产生的道德问题。本文从贝尔蒙报告角度来审视医疗器械临床试验的伦理问题，介绍了贝尔蒙报告产生的背景概念和医疗器械临床试验的概念及基本流程；贝尔蒙报告中的三项原则尊重个人、善行和平等公正原则在医疗器械临床试验中的体现以及针对贝尔蒙报告来解决医疗器械临床试验中产生的伦理问题的重大意义。通过知情同意的具体体现、对风险和好处的评估及受试者的选择和研究成果的分配三方面来解决临床试验中产生的伦理问题。     

Simulated Patient Studies: An Ethical Analysis

Context: In connection with health care reform, the U.S. Department of Health and Human Services commissioned a “mystery shopper,” or simulated patient study, to measure access to primary care. But the study was shelved because of public controversy over “government spying” on doctors. Opponents of the study also raised ethical concerns about the use of deception with human subjects without soliciting their informed consent. Methods: We undertook an ethical analysis of the use of simulated patient techniques in health services research, with a particular focus on research measuring access to care. Using a case study, we explored relevant methodological considerations and ethical principles relating to deceptive research without informed consent, as well as U.S. federal regulations permitting exceptions to consent. Findings: Several relevant considerations both favor and oppose soliciting consent for simulated patient studies. Making research participation conditional on informed consent protects the autonomy of research subjects and shields them from unreasonable exposure to research risks. However, scientific validity is also an important ethical principle of human subjects research, as the net risks to subjects must be justified by the value to society of the knowledge to be gained. The use of simulated patients to monitor access is a naturalistic and scientifically sound experimental design that can answer important policy‐relevant questions, with minimal risks to human subjects. As interaction between researchers and subjects increases, however, so does the need for consent. Conclusions: As long as adequate protections of confidentiality of research data are in place, minimally intrusive simulated patient research that gathers policy‐relevant data on the health system without the consent of individuals working in that system can be ethically justified when the risks and burdens to research subjects are minimal and the research has the potential to generate socially valuable knowledge.     

Randomized controlled trials in environmental health research: ethical issues

Randomized controlled trials (RCTs) are becoming increasingly common in environmental health research. Like all studies involving human subjects, environmental health RCTs raise many ethical challenges, ranging from obtaining informed consent to minimizing risks to protecting privacy and confidentiality. One of the most important issues raised by these studies is whether it is ethical to withhold effective environmental health interventions from research subjects in order to satisfy scientific objectives. Although environmental health investigators usually do not have professional obligations to provide medical care to research subjects, they have ethical obligations to avoid exploiting them. Withholding interventions from research subjects can be ethical, provided that it does not lead to exploitation of individuals or groups. To avoid exploiting individuals or groups, investigators should ensure that research subjects and study populations receive a fair share of the benefits of research.     

Ethics of Informed Consent for Pragmatic Trials with New Interventions

Objectives: Pragmatic trials evaluate the comparative benefits, risks, and burdens of health care interventions in real-world conditions. Such studies are now recognized as valuable to the perimarketing stage of drug development and evaluation, with early pragmatic trials (EPTs) being explored as a means to generate real-world evidence at the time of regulatory market approval. In this article, we present an analysis of the ethical issues involved in informed consent for EPTs, in light of the generally recognized concern that traditional ethical rules governing randomized clinical trials, such as lengthy informed consent procedures, could threaten the “real world” nature of such trials. Specifically, we examine to what extent modifications (waivers or alterations) to regulatory consent for EPTs would be ethical. Methods: We first identify broadly accepted necessary conditions for modifications of informed consent (namely, the research involves no more than minimal risk of harm, the research is impracticable with regulatory consent, and the alternative to regulatory consent does not violate legitimate patient expectations) and then apply those criteria to the premarket and early postmarket contexts. Results and Conclusions: The analysis shows that neither waivers nor alterations of regulatory consent for premarket EPTs will be ethically permissible. For postmarket EPTs with newly approved interventions, waivers of consent will be ethically problematic, but some studies might be conducted in an ethical manner with alterations to regulatory consent.     

Influence of the Nuremberg physicians' trials--beginning a new era in the ethical judging of human experiments

This short historical review attempts to shed light on the tortuous road on which society moved toward the general acceptance of the idea of experimenting on human beings. Unfortunately people had to realize that under antihuman or lenient political leadership, some physicians might apply their knowledge against their fellow beings, or might endanger them while pursuing their scientific goals. For this reason, it became necessary to codify the ethical requirements of medical experiments. This was done first by the Prussian government in 1900. The historical significance of the Nuremberg physicians' trials is that, by recognizing the enormous scientific importance of human experiments, they led to the formulation of general ethical principles governing human studies, which became known as the Nuremberg Code. Broad, international regulations were developed as the consequence of the trial. Unfortunately human experiments performed on prison inmates were judged at the trial as ethically acceptable, provided an informed consent was signed. Misusing this possibility many unethical experiments were done primarily in the US after the war. The great indignation due to ethical misconduct in prison trials and the highly unethical Tuskegee experiments performed on black Americans' suffering from syphilis, led much later to the organization of independent ethics committees. Through these committees, society exercises supervision of human trials. However, in case of severely ill patients the physician might be left alone to make a quick, and ethically correct, decision corresponding to the situation. In the final analysis the safety and ethical protection of research subjects remain the joint responsibility of society and of the experimenting physicians.     

Ethical implications of clinical trials in Tunisia

Clinical trials are necessary for medical advancement. They must respect legal obligations. Ethical questions related to protection of the human being's rights are yielded by these trials. Joining research to medical core is problematical in consideration of patient's consent to clinical trial. Exclusion by the Tunisian law of persons under age, pregnant or breast-feeding women from medical experimentation in the aim of protecting them against clinical research adverse events or abuses is ethically questionable since it deprives them from a possible medical progress. So why not to involve them in clinical research when there is an expected benefit, after bringing them protection as vulnerable persons like we should do for instance for the elderly, handicapped persons or prisoners. Legal creation of research ethics committees is important for the respect of experimentation rules on human beings.     

Italian regulation on the protection of human subjects participating to clinical studies, from the Nineties to 2004

In chronological order, and in the light of bioethics principles, the authors describe the Italian regulation which concerns the protection of human subjects participating in clinical trials from 1990 to July 2004, the related institution of Ethical Committees and the adoption of the tool of the informed consent. The publication includes the ties that have connected the Italian regulations to the European one since the beginning. During such period, the reception of the Good Clinical Practice guidelines - which occurred in 1992 first, and finally in 1997 - has led to the establishment and the fostering of such important institutions as well as to the shaping of a network of Ethical Committees working on clinical trials and coordinated at a central level. In this paper the authors examine in particular: clinical trials of medicinal products, of medical devices and of ionizing radiations. Some implications of ethics are also discussed.     

Ethics of clinical trials in family medicine

In this paper several issues are examined that arise from conducting randomized clinical trials in a family practice setting. The distinctive research tradition in family practice involves a patient's primary care physician performing an experimental investigation that usually, though not invariably, is focused on common health problems. Representative clinical trials are presented as examples that illustrate two ethical difficulties evoked by such research: a potential violation of the primary care physician's therapeutic imperative to provide the best possible treatment for his or her patient, and the likelihood that the type of physician-patient relationship fostered in family practice significantly diminishes the capacity of the patient to give true informed consent. In an attempt to resolve these ethical difficulties, a model of moral reasoning is presented that is based on easily understood ethical principles and is applicable to actual clinical decision making. Using that model, a tentative set of rules or guidelines is offered for implementing clinical trials in family medicine.     

Patients' perceptions of informed consent in acute myocardial infarction research: a Danish study

Seeking informed consent from patients in the acute phase of acute myocardial infarction (AMI) poses an ethical challenge due to the fact that these patients are under stress and require urgent medical attention. The very procedure of informed consent, which is supposed to protect eligible patients, may in fact cause harm due to a potential delay in the provision of therapy. Whether or not informed consent can and should be obtained under these particular circumstances is far from evident. Patients participating in various large-scale AMI trials have been enrolled with, as well as without, informed consent in recent years. Little is known, however, about how patients experience the informed consent process in the emergency situation of an AMI. This paper reports the results from qualitative interviews with 32 patients, who had to decide whether or not to participate in a large multi-centre clinical trial in Denmark. We analyse to what extent patients found the informed consent process acceptable as well as how various factors influenced their experience of the consent process. We argue that it is morally sound to involve those patients in a brief and concise informed consent process and that consent should be sought in such trials. Finally, we discuss how future AMI trials may nonetheless be improved by accommodating some of the concerns of the patients.     

药物临床研究中痴呆受试者知情同意过程探析

目的为我国痴呆药物临床研究受试者知情同意的规范化提供参考依据。方法对近年来我院关于痴呆药物的临床研究知情同意过程中所存在的问题及其原因进行分析,探究其解决方法。结果随机双盲安慰剂对照研究或针对中重度痴呆患者的研究中,受试者及其知情者的知情同意过程困难,不良事件发生率高,反之随机双盲阳性药对照或轻度痴呆患者的研究上述情况则较少出现。结论建议通过对受试者、知情者的健康教育及对研究者的法制教育,构造完善的法律法规保障制度,健全伦理委员会监督机制等措施来保护受试者及其知情者的权益。     

Are distinctive ethical principles required for cluster randomized controlled trials?

Cluster randomized trials are increasingly used in research into health care and health services. Ethics of individual patient randomized trials have been elucidated in a number of different codes, but less attention has been given to the ethical issues raised by cluster randomized trials. I assess the challenges raised by cluster randomized controlled trials by considering three questions: What are the essential elements of ethical medical research, particularly experiments on people? What are the features which distinguish cluster randomized controlled trials from ordinary RCTs? Do the distinctive features of cluster randomized trials entail new ethical principles, or careful application of existing principles? I conclude that cluster randomized controlled trials raise new issues on the nature and practice of informed consent, because of the levels at which consent can be sought, and for which it can be sought. In addition, careful consideration of the principles relating to the quality of the scientific design and analysis, balance of risk and benefit, liberty to leave a trial, early stopping of a trial and the power to exclude people from potential benefits is required.     

Sequential stopping rules in clinical trials

This paper reviews aspects of the development of sequential analysis of clinical trial data in medicine and suggests simple strategies for progress. The emphasis is on the pragmatic and ethical requirements of aspects of the design of phase III trials and in circumstances of genuine uncertainty characterized by much clinical experimentation. In particular consideration is given to the consequences of determining sample sizes from incorrect estimates of treatment effects. Armitage's work on sequential trials is traced to simple group sequential procedures based on repeated significance tests to minimize expected sample sizes in a wide class of experimental situations.     

Ethical challenges in cluster randomized controlled trials: experiences from public health interventions in Africa and Asia

Public health interventions usually operate at the level of groups rather than individuals, and cluster randomized controlled trials (RCTs) are one means of evaluating their effectiveness. Using examples from six such trials in Bangladesh, India, Malawi and Nepal, we discuss our experience of the ethical issues that arise in their conduct. We set cluster RCTs in the broader context of public health research, highlighting debates about the need to reconcile individual autonomy with the common good and about the ethics of public health research in low-income settings in general. After a brief introduction to cluster RCTs, we discuss particular challenges we have faced. These include the nature of – and responsibility for – group consent, and the need for consent by individuals within groups to intervention and data collection. We discuss the timing of consent in relation to the implementation of public health strategies, and the problem of securing ethical review and approval in a complex domain. Finally, we consider the debate about benefits to control groups and the standard of care that they should receive, and the issue of post-trial adoption of the intervention under test.     

The social control of human biomedical research: an overview and review of the literature

Social control mechanisms have become an important element of human medical research in the United States. At first largely intraprofessional, controls over human experimentation have moved increasingly in the direction of externally developed, bureaucratically administered, and formally sanctioned rules. This paper examines intra- and extraprofessional methods of control over biomedical science and reviews available research assessing their effectiveness in promoting researcher adherence to high ethical standards concerning the use of human subjects. Research suggests that intraprofessional controls (including medical training, peer influence, ethical codes, and disciplinary boards), are, on their own, inadequate to ensure investigator ethicality. However, studies examining external controls over biomedical research (government regulations, institutional review boards, judicial and state law), also suggest that extraprofessional regulations are often ineffective. Further study of both forms of scientific social control is needed, as well as research examining their interactive effects on investigators' ethical attitudes and practices.