Rieke van der Graaf

Revised CIOMS International Ethical Guidelines for Health-Related Research Involving Humans

The Council for International Organizations of Medical Sciences (CIOMS) was established jointly by the World Health Organization (WHO) and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949 as an international, nongovernmental, nonprofit organization and now includes 45 international, national, and associate member organizations, representing many of the biomedical disciplines, national academies of sciences, and medical research councils. CIOMS recently released a new version of its International Ethical Guidelines for Health-Related Research Involving Humans.1 These guidelines were developed in collaboration with WHO and based on authoritative ethical guidance documents, such as the World Medical Association’s Declaration of Helsinki2 and UNESCO’s Universal Declaration on Bioethics and Human Rights.3 The aim of the guidelines is to provide internationally vetted ethical principles and detailed commentary on how these principles should be applied, with particular attention to conducting research in lowand middleincome countries (LMICs).

Clarifying appeals to dignity in medical ethics from an historical perspective.

Over the past few decades the concept of (human) dignity has deeply pervaded medical ethics. Appeals to dignity, however, are often unclear. As a result some prefer to eliminate the concept from medical ethics, whereas others try to render it useful in this context. We think that appeals to dignity in medical ethics can be clarified by considering the concept from an historical perspective. Firstly, on the basis of historical texts we propose a framework for defining the concept in medical debates. The framework shows that dignity can occur in a relational, an unconditional, a subjective and a Kantian form. Interestingly, all forms relate to one concept since they have four features in common: dignity refers, in a restricted sense, to the special status of human beings; it is based on essential human characteristics; the subject of dignity should live up to it; and it is a vulnerable concept, it can be lost or violated. We argue that being explicit about the meaning of dignity will prevent dignity from becoming a conversation-stopper in moral debate. Secondly, an historical perspective on dignity shows that it is not yet time to dispose of dignity in medical ethics. At least Kantian and relational dignity can be made useful in medical ethics.

Equipoise should be amended, not abandoned

Background Benjamin Freedman has argued in 1987 that before a controlled trial is started, there should be ‘genuine uncertainty in the expert medical community about the preferred treatment’. Freedman’s definition of the concept is widespread in clinical research, but has been controversial since its start. Over the past decade, the equipoise controversy has become increasingly complex. Purpose This article aims: (1) to identify and clarify the main points of contention in the equipoise controversy, and (2) to reconcile the opposing views by pointing at areas of overlap between proponents and opponents in the equipoise debate. Methods We analyze the positions of the leading authors in the equipoise debate in the past decade. Results There is substantial overlap between the opponents and proponents of equipoise. Both should be able to accept the following answers to points of contention in the debate: (1) the therapeutic obligation can remain the basis for equipoise as long as it is conceived as an obligation to provide participants with competent care, (2) equipoise is grounded in a competent care and an epistemological dilemma, (3) equipoise does not as a rule prohibit placebo-controlled trials when proven effective treatment exists, (4) patient equipoise and individual physician equipoise are irrelevant, and (5) having to stop a trial is not always equivalent to disturbing equipoise. Clarification of these points of contention leads to a sharpened definition of equipoise: ‘a state of genuine agnosticism or conflict in the expert medical community about the net preferred medically established procedure for the condition under study’. This definition asks of physician-researchers and members of IRBs to meet two conditions: (1) to genuinely evaluate to what extent a proposed randomized clinical trial solves a state of agnosticism or a knowledge conflict in the expert medical community and (2) to respect the standard of competent care, meaning that they consider whether the regular clinical standard from an all-things considered perspective is also the preferred standard in the research context. Equipoise is a specification of two general ethical principles for clinical research: scientific validity and a favorable risk benefit ratio. As a specification equipoise adds substance to these principles since they do not explicitly ask for the two conditions. Equipoise is a prima facie obligation rather than a morally authoritative principle for determining the acceptability of clinical trials. It needs to be balanced against other norms for clinical research. Violation of equipoise is therefore not always unethical. Limitations This study is limited to the context of randomized clinical trials. Conclusions There is no decisive reason to give up on the equipoise requirement.Background Benjamin Freedman has argued in 1987 that before a controlled trial is started, there should be ‘genuine uncertainty in the expert medical community about the preferred treatment’. Freedman’s definition of the concept is widespread in clinical research, but has been controversial since its start. Over the past decade, the equipoise controversy has become increasingly complex.Purpose This article aims: (1) to identify and clarify the main points of contention in the equipoise controversy, and (2) to reconcile the opposing views by pointing at areas of overlap between proponents and opponents in the equipoise debate.Methods We analyze the positions of the leading authors in the equipoise debate in the past decade.Results There is substantial overlap between the opponents and proponents of equipoise. Both should be able to accept the following answers to points of contention in the debate: (1) the therapeutic obligation can remain the basis for equipoise as long as it is conceived as an obligation...

A systematic review of reasons for gatekeeping in palliative care research

Background: When healthcare professionals or other involved parties prevent eligible patients from entering a trial as a research subject, they are gatekeeping. This phenomenon is a persistent problem in palliative care research and thought to be responsible for the failure of many studies. Aim: To identify potential gatekeepers and explore their reasons for gatekeeping in palliative care research. Design: A ‘Review of Reasons’ based on the systematic Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach and a thematic synthesis. Data source: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature and PsycINFO from 2000 to May 20 2015 were searched. Studies in children (aged <18 years) and patients with dementia were excluded. Results: Thirty papers on gatekeeping in palliative care research were included. Five groups of potential gatekeepers were identified: healthcare professionals, research ethics committees, management, relatives and researchers. The fear of burdening vulnerable patients was the most reported reason for gatekeeping. Other reasons included ‘difficulty with disclosure of health status’, ‘fear of burdening the patient’s relatives’, ‘doubts about the importance or quality of the study’, ‘reticent attitude towards research and (research) expertise’ and ‘logistics’. In hospice and homecare settings, the pursuit of comfort care may trigger a protective attitude. Gatekeeping is also rooted in a (perceived) lack of skills to recruit patients with advanced illness. Conclusion: Gatekeeping is motivated by the general assumption of vulnerability of patients, coupled with an emphasis on the duty to protect patients. Research is easily perceived as a threat to patient well-being, and the benefits appear to be overlooked. The patients’ perspective concerning study participation is needed to gain a full understanding and to address gatekeeping in palliative care research.

What is the Best Standard for the Standard of Care in Clinical Research

During the past decennium, one of the main issues discussed in research ethics has been focused on the care that should be provided to the control group in a clinical trial. This discussion is also called the standard of care debate. Current international research ethics guidelines contain a wide variety of standards for the standard of care--including the provision of the highest attainable, the best available, the best current, a proven, and an established effective treatment. In this article, we systematically review the currently used standards and argue that none of the current standards is adequate to serve as a universal standard for the standard of care. Alex London has made a substantial proposal for a universal standard, but universally adopting his standard is problematic. In this article, we propose a revised version of Londons standard.During the past decennium, one of the main issues discussed in research ethics has been focused on the care that should be provided to the control group in a clinical trial. This discussion is also called the standard of care debate. Current international research ethics guidelines contain a wide variety of standards for the standard of care—including the provision of the highest attainable, the best available, the best current, a proven, and an established effective treatment. In this article, we systematically review the currently used standards and argue that none of the current standards is adequate to serve as a universal standard for the standard of care. Alex London has made a substantial proposal for a universal standard, but universally adopting his standard is problematic. In this article, we propose a revised version of Londons standard.

Adaptive Trials in Clinical Research: Scientific and Ethical Issues to Consider

INTEREST IN THE USE OF ADAPTIVE TRIAL DESIGN HAS INcreased among clinical investigators, pharmaceutical companies, and regulatory authorities. Adaptive trials are randomized clinical trials that allow for adaptations in the study design while the study is being conducted. Modifications as a study is being conducted can include changes in sample size, adjustments in medication dosage, or changes in the number of treatment groups. Adaptive trials can often decrease drug development time, which can have clinical and economic advantages. Adaptive trials also have certain ethical advantages because fewerparticipantsareassignedtotheinferiorprocedureordrug compared with trials with fixed designs. For instance, in the ASTIN trial, researchers conducted an adaptive phase 2 dose response trial to determine whether a neutrophil inhibitory factorimprovedrecoveryinpatientswithacuteischemicstroke; it did not. However, this trial needed to enroll 966 patients, compared with the need to enroll 1080 patients if a traditional designhadbeenused.Furthermore, theadaptivedesignmade it possible to stop the trial early for futility. However, certain features of adaptive trials may create some potential scientific and ethical challenges. This Viewpoint explores several ethical issues that researchers and participants in adaptive trials should consider.

Brief Report : Staged-informed Consent in the Cohort Multiple Randomized Controlled Trial Design

The “cohort multiple randomized controlled trial,” a new design for pragmatic trials, embeds multiple trials within a cohort. The cohort multiple RCT is an attractive alternative to conventional RCTs in fields where recruitment is slow, multiple new (competing) interventions for the same condition have to be tested, new interventions are highly preferred by patients and doctors, and the risk of disappointment bias, cross-over, and contamination is considerable. To prevent these unwanted effects, the cohort multiple RCT provides information on randomization to the intervention group/arm only, and only after randomization (i.e., prerandomization). To some, especially in a clinical setting, this is not ethically acceptable. In this article, we argue that prerandomization in the cohort multiple randomized controlled trial (cmRCT) can be avoided by adopting a staged-informed consent procedure. In the first stage, at entry into the cohort, all potential participants are asked for their informed consent to participate in a cohort study and broad consent to be either randomly selected to be approached for experimental interventions or to serve as control without further notice during participation in the cohort. In a second stage, at the initiation of an RCT within the cohort, informed consent to receive the intervention is then only sought in those randomly selected for the intervention arm. At the third stage, after completion of each RCT, all cohort participants receive aggregate disclosure of trial results. This staged-informed consent procedure avoids prerandomization in cmRCT and aims to keep participants actively engaged in the research process.

Justification of exclusion criteria was underreported in a review of cardiovascular trials

OBJECTIVES Ethical guidelines for human subject research require that the burdens and benefits of participation be equally distributed. This study aimed to provide empirical data on exclusion of trial participants and reasons for this exclusion. As a secondary objective, we assessed to what extent exclusion affects generalizability of study results. STUDY DESIGN AND SETTING Review of trials on secondary prevention of cardiovascular events. RESULTS One hundred thirteen trials were identified, of which 112 reported exclusion criteria. One study justified the exclusion criteria applied. Ambiguous exclusion criteria due to the opinion of the physician (28 of 112 = 25%) or physical disability (12 of 112 = 11%) were reported. Within groups of trials that studied similar treatments (ie, beta-blocker, clopidogrel, or statin therapy), baseline characteristics differed among trials. For example, the proportion of women ranged between 23.1-47.4%, 2.1-38.9%, and 10.6-50.6% for the clopidogrel, beta-blocker, and statin trials, respectively. Nevertheless, no evidence was found for heterogeneity of treatment effects. CONCLUSION Almost none of the articles justified the applied exclusion criteria. No evidence was found that inclusion of dissimilar participants affected generalizability. To allow for a normative discussion on equitable selection of study populations, researchers should not only report exclusion criteria but also the reasons for using these criteria.

Strengths and weaknesses of guideline approaches to safeguard voluntary informed consent of patients within a dependent relationship

BackgroundIt is thought that a dependent relationship between patients and physicians who enroll their own patients in research compromises voluntary informed consent. Therefore, several ethical guidelines for human subject research provide approaches to mitigate these compromises. Currently, these approaches have not been critically evaluated. In this article, we analyze the approaches of ethical guidelines to manage the influence of a dependent relationship between patients and physicians on voluntary informed consent and discuss the strengths and weaknesses of these approaches.MethodsWe performed a review of international ethical guidance documents on human subject research, listed in the Oxford Textbook of Clinical Research Ethics and found through cross referencing. We also searched Global Ethics Observatory (GEObs) and the World Health Organization (WHO) website. Guidelines from all years were eligible for inclusion. The date last searched was December 2013.DiscussionWe identified two basic guideline approaches: 1. a process approach, which focuses on the person who obtains informed consent, that is, an independent individual, such as a research nurse or counselor; and 2. a content approach, emphasizing the voluntary nature of participation. Both approaches are valuable, either because the influence of the physician may diminish or because it empowers patients to make voluntary decisions. However, the approaches also face challenges. First, research nurses are not always independent. Second, physician-investigators will be informed about decisions of their patients. Third, involvement of a counselor is sometimes unfeasible. Fourth, the right to withdraw may be difficult to act upon in a dependent relationship.ConclusionsCurrent guideline approaches to protect voluntary informed consent within a dependent relationship are suboptimal. To prevent compromises to voluntary informed consent, consent should not only be obtained by an independent individual, but this person should also emphasize the voluntary nature of participation. At the same time, dependency as such does not imply undue influence. Sometimes the physician may be best qualified to provide information, for example, for a very specialized study. Still, the research nurse should obtain informed consent. In addition, patients should be able to consult a counselor, who attends the informed consent discussions and is concerned with their interests. Finally, both physicians and research nurses should disclose research interests.

The ethics of cluster-randomized trials requires further evaluation: a refinement of the Ottawa Statement

OBJECTIVES The Ottawa Statement is the first guidance document for the ethical and scientific conduct of cluster-randomized trials (CRTs). However, not all recommendations are straightforward to implement. In this paper we will reflect in particular on the recommendation on identifying human research subjects and the issue to what extent the randomization process should be disclosed if there is a risk of contamination. STUDY DESIGN AND SETTING The Ottawa Statement was thoroughly evaluated within a multidisciplinary research team, consisting amongst others of epidemiologists and ethicists. RESULTS Patients in a CRT may also be considered as research subjects if they are indirectly affected by the studied interventions in a CRT. Second, health care workers are research subjects in CRTs but have a different moral status compared with ordinary research participants. This different status has implications for withdrawal and the choice of the primary objective. Third, modified informed consent for CRTs may be obtained when researchers can demonstrate that disclosure of the randomization process would affect the validity of a CRT. CONCLUSION Recommendations of the Ottawa Statement on identifying the research subject and providing informed consent can and should be refined.