Charles Weijer

The increasing use of cluster randomised trials in low-resource settings raises unique ethical issues. TheOttawa Statement on the Ethical Design and Conduct of Cluster Randomised Trialsis the first international ethical guidance document specific to cluster trials, but it is unknown if it adequately addresses issues in low-resource settings. In this paper, we seek to identify any gaps in theOttawa Statementrelevant to cluster trials conducted in low-resource settings. Our method is (1) to analyse a prototypical cluster trial conducted in a low-resource setting (PURE Malawi trial) with theOttawa Statement; (2) to identify ethical issues in the design or conduct of the trial not captured adequately and (3) to make recommendations for issues needing attention in forthcoming revisions to theOttawa Statement. Our analysis identified six ethical aspects of cluster randomised trials in low-resource settings that require further guidance. The forthcoming revision of theOttawa Statementshould provide additional guidance on these issues: (1) streamlining research ethics committee review for collaborating investigators who are affiliated with other institutions; (2) the classification of lay health workers who deliver study interventions as health providers or research participants; (3) the dilemma experienced by investigators when national standards seem to prohibit waivers of consent; (4) the timing of gatekeeper engagement, particularly when researchers face funding constraints; (5) providing ancillary care in health services or implementation trials when a routine care control arm is known to fall below national standards and (6) defining vulnerable participants needing protection in low-resource settings.

Functional MRI shows promise as a candidate prognostication method in acutely comatose patients following severe brain injury. However, further research is needed before this technique becomes appropriate for clinical practice. Drawing on a clinical case, we investigate the process of obtaining informed consent for this kind of research and identify four ethical issues. After describing each issue, we propose potential solutions which would make a patient’s participation in research compatible with her rights and interests. First, we defend the need for traditional proxy consent against two alternative approaches. Second, we examine the impact of the intensive care unit environment on the informed consent process. Third, we discuss the therapeutic misconception and its potential influence on informed consent. Finally, we deal with issues of timing in recruiting participants and related factors which may affect the risks of participation.

Randomized controlled trial trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions, whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. Semi-structured interviews with key stakeholders, across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications.

The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of clinical equipoise have put forward alleged counter-examples to this restriction—describing instances of ethical placebo-controlled trials that apparently violate clinical equipoise. In this essay, we respond to these examples and show that clinical equipoise is not as restrictive of placebos as these authors assume. We argue that a subtler appreciation for clinical equipoise—in particular the distinction between de facto and de jure interpretations of the concept—allows the concept to explain when and why a placebo control may be necessary to answer a question of clinical importance.

OBJECTIVES: To compare 2005 and 1995 ethics guidelines from journal editors to authors regarding requirements for institutional review board (IRB) approval and conflict-of-interest (COI) disclosure. DESIGN: A descriptive study of the ethics guidelines published in 103 English-language biomedical journals listed in the Abridged Index Medicus in 1995 and 2005. Each journal was reviewed by the principal author and one of four independent reviewers. RESULTS: During the period, the proportion of journals requiring IRB approval increased from 42% (95% CI 32.2% to 51.2%, p<0.001) to 76% (95% CI 66.4% to 83.1%, p<0.001). In 2005, an additional 9% referred to the Declaration of Helsinki or the International Committee of Medical Journal Editors' Uniform requirements for ethical guidelines; 15% (95% CI 8.5% to 22.5%, p<0.01) provided ambiguous or no requirements. The proportion of journals requiring COI disclosure increased from 75% (95% CI 66.6% to 83.3%, p<0.05) to 94% (95% CI 89.4% to 98.6%, p<0.05); 41% had comprehensive requirements, while some addressed only funding source (6%), were vague (10%) or both (14%). Criteria for authorship rose from 40% (95% CI 30.5% to 49.5%, p<0.05) to 72% (95% CI 63.3% to 80.7%, p<0.05). Journals with higher impact factors were more likely to require IRB approval (p<0.01). Journals in anaesthesia and radiology all required IRB approval; requirements in other disciplines varied. CONCLUSIONS: Instructions to authors regarding ethical standards have improved. Some remain incomplete, especially regarding the scope of disclosure of COI. The ethical guidelines presented to authors need further clarification and standardisation

Objective Cluster randomised trial (CRT) investigators face challenges in seeking informed consent from individual patients (cluster members). This study examined associations between reporting of patient consent in healthcare CRTs and characteristics of these trials. Study design Consent practices and study characteristics were abstracted from a random sample of 160 CRTs performed in primary or hospital care settings that were published from 2000 to 2008. Multivariable logistic regression was used to examine associations between reporting of patient consent and methodological characteristics, as well as publication features such as date and journal of publication. Results 82 (53.8%) of 160 studies reported obtaining informed consent from individual patients. Reporting of patient consent was independently and positively associated with: smaller cluster size, the evaluation of experimental interventions targeted at patients, data collection from individual patients, publication later than 2004 and publication in higher-impact journals. Conclusions Reporting of consent practices in published CRTs should be improved. Consent practices in published CRTs appear to be related to the type of interventions under study, as well as journal impact and trends in research ethics practices. These findings will inform best practices in trial conduct and ethics review, remediation of errors in consent practices and ethics review and the development of regulatory guidance for CRTs

Purposeful infection of healthy volunteers with a microbial pathogen seems at odds with acceptable ethical standards, but is an important contemporary research avenue used to study infectious diseases and their treatments. Generally termed ‘controlled human infection studies’, this research is particularly useful for fast tracking the development of candidate vaccines and may provide unique insight into disease pathogenesis otherwise unavailable. However, scarce bioethical literature is currently available to assist researchers and research ethics committees in negotiating the distinct issues raised by research involving purposefully infecting healthy volunteers. In this article, we present two separate challenge studies and highlight the ethical issues of human challenge studies as seen through a well-constructed framework. Beyond the same stringent ethical standards seen in other areas of medical research, we conclude that human challenge studies should also include: (i) independent expert reviews, including systematic reviews; (ii) a publicly available rationale for the research; (iii) implementation of measures to protect the public from spread of infection beyond the research setting; and (iv) a new system for compensation for harm. We hope these additions may encourage safer and more ethical research practice and help to safeguard public confidence in this vital research alternative in years to come.

The ethics of the Flexibility In duty hour Requirements for Surgical Trainees trial have been vehemently debated. Views on the ethics of the FIRST trial range from it being completely unethical to wholly unproblematic. The FIRST trial illustrates the complex ethical challenges posed by cluster randomised trials of policy interventions involving healthcare professionals. In what follows, we have three objectives. First, we critically review the FIRST trial controversy, finding that commentators have failed to sufficiently identify and address many of the relevant ethical issues. The 2012 Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides researchers and research ethics committees with specific guidance for the ethical design and conduct of CRTs. Second, we aim to demonstrate how the Ottawa Statement provides much-needed clarity to the ethical issues in the FIRST trial, including: research participant identification; consent requirements; gatekeeper roles; benefit-harm analysis and identification of vulnerable participants. We nonetheless also find that the FIRST trial raises ethical issues not adequately addressed by the Ottawa Statement. Hence, third and finally, we raise important questions requiring further ethical analysis and guidance, including: Does clinical equipoise apply to policy interventions with little or no evidence-base? Do healthcare providers have an obligation to participate in research? Does the power-differential in certain healthcare settings render healthcare providers vulnerable to duress and coercion to participant in research? If so, what safeguards might be implemented to protect providers, while allowing important research to proceed?

Pragmatic comparative effectiveness randomized controlled trials evaluate the effectiveness of one interventions under real-world clinical conditions. The results of ceRCTs are often directly generalizable to everyday clinical practice, providing information critical to decision-making by patients, clinicians, and healthcare policymakers. The PRECIS-2 framework identifies nine domains that serve to score a trial on a continuum between very explanatory to very pragmatic. According to the framework, pragmatic trials may have one or more of the following features: there are fewer eligibility criteria for participants, in an...

Abstract:The ethical principle of autonomy requires physicians to respect patient autonomy when present, and to protect the patient who lacks autonomy. Fulfilling this ethical obligation when a patient has a communication impairment presents considerable challenges. Standard methods for evaluating decision-making capacity require a semistructured interview. Some patients with communication impairments are unable to engage in a semistructured interview and are at risk of the wrongful loss of autonomy. In this article, we present a general strategy for assessing decision-making capacity in patients with communication impairments. We derive this strategy by reflecting on a particular case. The strategy involves three steps: (1) determining the reliability of communication, (2) widening the bandwidth of communication, and (3) using compensatory measures of decision-making capacity. We argue that this strategy may be useful for assessing decision-making capacity and preserving autonomy in some patients with communication impairments.

Wittgenstein, in his famous critique of philosophy, noted that the influence of an idea can be such that it alters the way that we see the world. “It is like a pair of glasses on our nose through which we see whatever we look at,” he said. “It never occurs to us to take them off.” This view of the power of an idea suggests that the interpretation of an event, and what response this event calls for, can depend upon the view one has of the world. A person who is naive about medical facts may, for example, interpret chest pain upon exertion as a sign that he is “overdoing it”; were he more medically knowledgeable, the same symptom might be interpreted as a possible indicator of coronary artery disease. The naive interpretation calls for rest; the informed interpretation calls for medical attention as well.

Owing to unique features of their design, cluster randomized trials complicate the interpretation of standard ethics guidelines. The recently published Ottawa statement on the ethical design and conduct of cluster randomized trials provides researchers and research ethics committees with detailed guidance on the design, conduct, and review of cluster trials. The Ottawa statement sets out 15 recommendations, including guidance on the justification of study design, the need for research ethics committee review, the identification of research participants, obtaining informed consent, the role of gatekeepers in protecting cluster interests, the assessment of benefits and harms, and the protection of vulnerable participants.

The use of statistics in medical research has been compared to a religion: it has its high priests, supplicants, and orthodoxy. Although the comparison may be more unfair to religion than to research, a useful lesson can nonetheless be drawn: the practice of clinical research may benefit—as does the spirit—from critical self-examination. Arguably, no aspect of the conduct of clinical trials is currently more controversial—and thus in as dire need of critical examination—than the use of placebo controls. The ethical and scientific controversies associated with placebo-controlled trials, never far below the surface, have once again seized public attention. Clearly, concern about these issues within the professional community runs deep and wide, as evidenced by the volume of response generated by Kenneth Rothman and Karin Michels's recent Critique. Criticisms of the use of placebo controls in clinical research are scattered through the literatureo; our objective is to present the case against placebos in a compendious form that takes account of scientific and statistical as well as normative issues.

Placebo-controlled trials are held by many, including regulators at agencies like the United States Food and Drug Administration, to be the gold standard in the assessment of new medical interventions. Yet the use of placebo controls in clinical trials has been the focus of considerable controversy. In this two-part article, we challenge a number of common beliefs concerning the value of placebo controls. Part I critiques statistical and other scientific justifications for the use of placebo controls in clinical research. The continued use of placebo controls in clinical trials on diseases for which accepted treatment exists raises equally important ethical, legal, and regulatory issues for which various justifications have been given. Defense of this practice relies on normative as well as empirical myths.In their attack on the prevailing use of placebo controls, Kenneth Rothman and Karin Michels emphasize that this practice stands in violation of the World Medical Association's guidelines on the ethics of human experimentation, most commonly known as the Helsinki Declaration.

In this issue of the Journal of Law, Medicine & Ethics Peter Clark provides a comprehensive and sound ethical analysis of clinical trials examining the treatment of advanced Parkinson's disease with fetal tissue transplantation. These studies raise profound questions about how clinical trials of surgical interventions ought to be conducted. At stake is not only the ethical basis of such trials, but differing views as to the proper role of science in medicine and its limitations.Experience with the broader debate on the ethical permissibility of placebo controls has taught us that the choice of control treatment is an aspect of trial design in which ethical and scientific issues overlap. Accordingly, I will highlight, and perhaps expand upon, three issues raised by Clark: What scientific questions ought clinical trials of surgical interventions ask? How should the ethical analysis of risk for such trials be conceived? And, are surgical patients a vulnerable population?

The institutional review board is the social-oversight mechanism charged with protecting research subjects. Performing this task competently requires that the IRB scrutinize informed-consent procedures, the balance of risks and potential benefits, and subject-selection procedures in research protocols. Unfortunately, it may be said that IRBs are spending too much time editing informed-consent forms and too little time analyzing the risks and potential benefits posed by research. This time mismanagement is clearly reflected in the research ethics literature. A review of articles published between 1979 and 1990 in IRB: A Review of Human Subjects Research, for example, reveals a large number of articles on informed consent and confidentiality and considerably fewer on the assessment of risks and potential harms, study design, and subject-selection procedures.

Bioethics is currently witnessing unprecedented debate over the moral and legal norms governing the conduct of clinical research. At the center of this debate is the duty of care in clinical research, and its most widely accepted specification, clinical equipoise. In recent work, we have argued that equipoise and cognate concepts central to the ethics of clinical research have been left unnecessarily vulnerable to criticism. We have suggested that the vulnerability lies in the conspicuous absence of an articulated foundation in moral and legal theory of the physician-researcher's duty of care to the patient-subject. We have repeatedly suggested that the requisite foundation is in the ethics of trust and the law of fiduciaries.Curiously, despite the absence of a published thorough exposition of our position, some have preemptively criticized our suggestion that the relationship between physician-researcher and patient-subject is fiduciary. Others have offered their own accounts of the implications of fiduciary law for the relationship.

Is there no balm in Gilead; is there no physician there? Why then is not the health of the daughter of my people recovered?In July of 2004, Cambodian sex workers staged a protest of an HIV prevention trial set to enroll 900 sex workers in Phnom Penh, charging the study planners with exploitation. The Cambodian study was one of a series of international clinical trials sponsored by the U.S. National Institutes of Health, U.S. Centers for Disease Control and Prevention, and the Bill and Melinda Gates Foundation testing the safety and efficacy of tenofovir, an antiretroviral drug produced by Gilead Sciences, Inc., to prevent HIV transmission. To date, two of these international studies have been closed and one is suspended, prompting calls for re-examination of the ethics of HIV prevention trials.

After severe brain injury, one of the key challenges for medical doctors is to determine the patient’s prognosis. Who will do well? Who will not do well? Physicians need to know this, and families need to do this too, to address choices regarding the continuation of life supporting therapies. However, current prognostication methods are insufficient to provide a reliable prognosis. Functional Magnetic Resonance Imaging (MRI) holds considerable promise for improving the accuracy of prognosis in acute brain injury patients. Nonetheless, research on functional MRI in the intensive care unit context is ethically challenging. These studies raise several ethical issues that have not been addressed so far. In this article, Prof. Charles Weijer and his co-workers provide a framework for researchers and ethics committees to design and review these studies in an ethically sound way.