Scientific research on human subjects and ethics procedures at the Istituto Superiore di Sanità: a survey of the articles issued in 2001

Principles promoting the protection of subjects involved in biomedical research are interpreted differently within the scientific community. The purpose of this paper is to describe the attitudes of researchers working at the Istituto Superiore di Sanità (ISS) regarding the ethical implications of studies involving human beings, with particular emphasis on aspects concerning informed consent (IC) and ethics committee (EC) review. In 2001, ISS researchers published a total of 733 articles, 93 (12.7%) of which were studies involving human beings. Nearly 2/3 (60/93) were epidemiological, while the remaining 35.5% were based on laboratory data. Half (47/93) reported physical or psychological interventions or treatments on study subjects. 40.9% of articles mentioned that informed consent had been obtained and only 12.9% that approval had been given by an ethics committee. The low proportion of articles on which a protocol had been submitted the EC was due in part to the type of studies, but also to the absence of an institutional EC prior to 2001. Ethical procedures were more present in laboratory than in epidemiologic studies (IC: 69.7% vs 25.0%, p < 0.001) (EC: 27.3% vs 5.0% p = 0.004). Those differences were more likely due to the less interventionist nature of the epidemiologic studies rather than in poor ethical awareness on the part of epidemiologists. Further efforts are needed to develop and enforce clear institutional policies regarding ethical procedures.     

Time for professionalising the system of medical ethics review in the Netherlands

In two recent papers, a radical change of the review system for medical ethics review committees was proposed. The current systems in Great Britain and Australia were described and it was suggested that the extended roles and responsibilities of the medical ethics review committees could not be fulfilled by the present committees. It was proposed that professional medical ethics committees be established with full time members who would receive an appropriate honorarium. The Netherlands has a decentralised system of medical ethics review, which is based on peer review. A radical change of the current system of medical ethics review is not warranted. There is however a need for further improvements to the current peer-review system. An important aspect of this improvement is an honorarium for the members as well as a budget for training and for the adequate scientific and administrative support of the committee by a secretariat. The fees levied for reviewing each protocol could in part finance the committee and its secretariat. However, these fees will probably not meet all of the costs. Therefore the centres involved in medical research should consider supporting their committees. It is in their interest to demonstrate their wish to protect those persons who consent to participate as research subjects. This will maintain the confidence of both the public and future participants in clinical trials. Furthermore, an efficient and adequate system of ethical review will support a balanced view towards medical research with human subjects and will also contribute to a positive image of the centre also as an attractive environment for medical professionals.     

Oops,what about ethics?

Ethics approval of research studies is essential for the protection and rights of study subjects, whether this is for prospective research or record reviews. This article shares a painful lesson learned from a field experience where the appropriate steps for obtaining ethics approval were not followed by a young researcher. This researcher had embarked on an operational research project, but had omitted to seek ethics approval from a local ethics committee. Young researchers, particularly from low- and middle-income countries, need to learn about the importance and value of ethics.     

Comparaison des comités d’éthique de France et du Québec en regard de l’incapacité à consentir à la recherche

BackgroundFrench and Quebec legislation allow the inclusion of decisionally-incompetent subjects in research, provided certain conditions are met. In both jurisdictions, ethics committees are charged with ensuring that research protocols meet these conditions. We investigated committee members’ knowledge and opinions regarding substitute consent for research purposes.MethodsTwo consecutive postal surveys were conducted among all members of ethics committees from France and Quebec. Knowledge and opinions about proxy consent were measured with clinical vignettes describing hypothetical situations involving incapable adults. For each vignette, respondents were asked to either identify the person legally authorized to consent or choose the substitute decision-maker whom they considered best suited to do so.ResultsKnowledge of the legislation governing substitute consent was poor in both samples, especially in situations involving an incompetent person who did not have a legal representative. Knowledge was worse among French ethics committee members (p < 0.001). In hypothetical clinical studies that involved no risk to the subject's health, 59% of respondents favored consent from a close relative. As the risk increased, the proportion gradually decreased to 14.2%, while the proportion against soliciting the cognitively impaired older adult tended to increase (from 5.8 to 31.2%). These trends were observed in both samples.ConclusionThese findings underscore the need to better educate ethics committee members about legislation regarding prospective subjects who lack decisional capacity. Such efforts could improve both knowledge of and compliance with legal provisions that enable or restrict the participation of cognitively-impaired patients in research projects. Moreover, study findings provide some support for enlarging the category of persons who are authorized to consent to low-risk research on behalf of incapacitated adults who lack legal representation.     

Trust in early phase research: therapeutic optimism and protective pessimism

Bioethicists have long been concerned that seriously ill patients entering early phase (‘phase I’) treatment trials are motivated by therapeutic benefit even though the likelihood of benefit is low. In spite of these concerns, consent forms for phase I studies involving seriously ill patients generally employ indeterminate benefit statements rather than unambiguous statements of unlikely benefit. This seeming mismatch between attitudes and actions suggests a need to better understand research ethics committee members’ attitudes toward communication of potential benefits and risks of early phase studies to potential subjects. We surveyed the members of two U.S. research ethics committees using a phase I gene transfer study scenario, and compared the results to a previous survey of potential subjects’ perceptions and attitudes toward benefit and risk for the same protocol. The results show that there is indeed a gap between the subjects’ perceptions and the committee members’ views on what is appropriate to be communicated to research subjects. This discrepancy is the product of both the commonly assumed optimism of the subjects and to a “protective pessimism” of the research ethics committee members. We discuss this discrepancy using “frameworks of trust” and demonstrate the need to incorporate these frameworks into the existing model of informed consent.

The Role of Community Advisory Boards: Involving Communities in the Informed Consent Process

Ethical research involving human subjects mandates that individual informed consent be obtained from research participants or from surrogates when participants are not able to consent for themselves. The existing requirements for informed consent assume that all study participants have personal autonomy; fully comprehend the purpose, risks, and benefits of the research; and volunteer for projects that disclose all relevant information. Yet contemporary examples of lapses in the individual informed consent process have been reported. The authors propose the use of community advisory boards, which can facilitate research by providing advice about the informed consent process and the design and implementation of research protocols. These activities could help reduce the number of individual informed consent lapses, benefiting study participants and the scientific integrity of the research in question.     

Analysis of Master theses in nursing under the spotlight of bioethics

The goal of this study is to investigate the application of ethical principles in research with people in the master's thesis of students of the Nursery Master's Course at the Federal University of Ceará (UFC). The theoretical reference were the principles of Bioethics of benevolence/maleficence, autonomy and justice, the 196/96 resolution and Coren's Resolution 240/2000. It was concluded that students have always followed some basic ethical principles; researcher's conduct has not changed after the adoption of Resolution 196/96; in spite of obligatoriness of sending research projects to Ethics and Research Council (CEP); most of the researchers did not fulfill that requirement; the principle most approached in Bioethics was autonomy with emphasis on informed consent and secrecy.     

'Informed consent' and prerandomization

The usual procedure in randomised controlled trials is to obtain informed consent first, after which participants can be randomised. The reversal of the order, first randomisation and then informed consent, is called pre-randomisation (Zelen design). In the Netherlands, there is discussion as to whether pre-randomisation should be allowed in medical research. Full informed consent regarding the design of the investigation may lead to unwanted loss of distinction between the experimental and control groups, thus reducing the internal validity of the investigation. A possible solution could be to include, in the informed consent procedure, the statement that certain information has been withheld because revealing it now would make the investigation useless, but that it will be revealed to all participants afterwards and that the study design was approved by the medical ethics committee. In this way, the advantage of the enhanced internal validity of the pre-randomisation design is retained while simultaneously keeping intact the sequence of first informed consent and then randomisation.     

A welcome guide for evaluating medical research involving human subjects

In 1999, the Dutch Medical Research Involving Human Subjects Act came into force. The principal aim of this Act is to provide protection for human subjects who take part in medical research. Medical research involving human subjects may only be carried out after it has been approved by a recognised medical ethics committee. A central committee (Dutch acronym: CCMO) regulates the recognition of the local medical ethics committees and monitors their performance. For some types of research the protocol has to be reviewed by the CCMO itself. These are: non-therapeutic research involving children and mentally incompetent patients and research on gene therapy, xenotransplantation and embryos. The CCMO has recently published a guide for the local medical ethics committees. It presents an excellent overview of all the legal and practical aspects of the work of medical ethics committees. The guide is highly recommended.     

Research Ethics Committee Auditing: The Experience of a University Hospital

The authors report the first Italian experience of a research ethics committee (REC) audit focused on the evaluation of the REC’s compliance with standard operating procedures, requirements in insurance coverage, informed consent, protection of privacy and confidentiality, predictable risks/harms, selection of subjects, withdrawal criteria and other issues, such as advertisement details and justification of placebo. The internal audit was conducted over a two-year period (March 2009–February 2011) divided into quarters to better value the influence of the new insurance coverage regulation that came into effect in March 2010 (Ministerial Decree of 14 July, 2009) and expand the requirements to safeguard participants in clinical drug trials including other critical items as information and consent and the risks to benefits ratio. Out of a total of 639 REC’s opinions and research studies, 316 were reviewed. Regarding the insurance policy requirements, Auditor/REC non-compliance occurred only in one case. The highest number of Auditor/REC non-compliance was in regard to information and consent, which should have incurred a suspended decision rather than a favorable opinion. This internal audit shows the importance and the difficulty of the review process. For this reason, specific courses for members of the research ethics committee and for those who aspire to become auditors will be provided. There may also be efforts to improve the standard operating procedures already in place.     

Conducting research in developing countries: experiences of the informed consent process from community studies in Peru

This article discusses the process for obtaining genuine informed consent for the participation of human subjects in research in developing countries. We discuss the consent process in the light of recently published guidelines, the experience of nutrition and health research projects, and the ethics review process of the Instituto de Investigacion Nutricional with peri-urban and rural populations in Peru. We discuss the cultural context in relation to (i) who should be involved in the decision for participation, especially for research in children and in community settings; (ii) when to use written or verbal consent; (iii) the format and presentation of the consent form to ensure understanding by the target population; and (iv) the process of how and by whom information is given and consent is obtained. Common concerns of participants with regard to their involvement in research studies are presented, as well as aspects that participants find difficult to understand. Some specific concerns of conducting research with Indigenous Peoples are discussed. We recommend future research to further understand and implement informed consent processes to assure genuine and voluntary consent in different developing country contexts.     

医学期刊编辑对生物医学研究伦理问题的处理方式调研及建议

【目的】 探讨医学期刊编辑处理生物医学研究伦理问题的方式,为推动确立医学期刊伦理审查规范提供参考。【方法】 通过问卷星向国内医学期刊编辑发放调查问卷,对审稿时和论文出版后处理医学伦理相关问题的方式展开调研。【结果】 共回收问卷230份。调查显示:在审稿阶段,在保护患者隐私方面,英文期刊、中英双语期刊的编辑更注重要求作者提供授权同意相关证明材料;中、英文期刊以及中英双语期刊的编辑对涉及人体试验伦理问题的处理方式都比较规范。但是,对于研究是否获得患者知情同意、动物实验研究是否经过伦理委员会审查、回顾性研究是否需要伦理审查、涉及人的研究是否在临床试验注册中心注册等问题,编辑还需要进一步重视。在论文出版后,编辑发现的医学伦理问题主要是“涉及人的研究未说明是否经过伦理委员会审查”。对论文出版后发现的没有保护患者隐私和没有在临床试验注册中心注册的问题,大部分期刊缺乏相关处理方案。【结论】 编辑应加强对论文知情同意、动物实验伦理、回顾性研究伦理的审查,并审查涉及人的研究是否在临床试验注册中心注册,以推动我国医学期刊的高质量发展。     

Consent revisited: the impact of return of results on participants' views and expectations about trial participation

BackgroundIncreasingly, the sharing of study results with participants is advocated as an element of good research practice. Yet little is known about how receiving the results of trials may impact on participants'' perceptions of their original decision to consent.ObjectiveWe explored participants'' views of their decision to consent to a clinical trial after they received results showing adverse outcomes in some arms of the trial.MethodSemi‐structured interviews were conducted with a purposive sample of 38 women in the UK who participated in a trial of antibiotics in pregnancy. All had received results from a follow‐up study that reported increased risk of adverse outcomes for children of participants in some of the trial intervention arms. Data analysis was based on the constant comparative method.ResultsParticipants'' original decisions to consent to the trial had been based on hope of personal benefit and assumptions of safety. On receiving the results, most made sense of their experience in ways that enabled them to remain content with their decision to take part. But for some, the results provoked recognition that their original expectations might have been mistaken or that they had not understood the implications of their decision to participate. These participants experienced guilt, a sense of betrayal by the maternity staff and researchers involved in the trial, and damage to trust.ConclusionsSharing of study results is not a wholly benign practice, and requires careful development of suitable approaches for further evaluation before widespread adoption.     

The Attitudes of Females in Drug Court Toward Additional Safeguards in HIV Prevention Research

This article examines the attitudes of 97 women from the St. Louis City Drug Court who previously participated in an HIV prevention study. Data from the previous study indicated that the women met multiple criteria for vulnerability in research. Federal regulations require that such participants be provided with “additional safeguards.” The survey explored the following questions: (1) What are participants’ attitudes toward commonly proposed additional safeguards for vulnerable participants in research, and (2) Are attitudes toward safeguards related to participants’ previous compliance with an HIV prevention protocol? Preferences regarding safeguards in research were not significantly related to participants’ compliance in the previous study. Most participants wanted researchers to take extra measures not only to provide consent information, but to ensure that they are not high on drugs, that they understand relevant information, and that they retain consent information at each visit. Most participants wanted researchers themselves, and not a third party, to assume this responsibility.     

Confusions in the equipoise concept and the alternative of fully informed overlapping rational decisions

Despite its several variations, the central position of equipoise is that subjects in clinical experiments should not be randomized to conditions when others believe that better alternatives exist. This position has been challenged over issues of which group in the medical or research community is authorized to make that determination, and it has been argued that informed consent provides sufficient ethical protection for participants independent of equipoise. In this paper I frame ethical participation in clinical research as a two-party decision process involving offering and accepting participation under informed consent. Nine conditions are identified in which it is possible that potential participants and researchers or care professionals can rationally choose divergent actions based on identical understandings of the situation. Under such circumstances, researchers or care professionals cannot ethically substitute their understanding of equipoise in the situation for the patients’ choices, or vice versa.     

Views of US researchers about informed consent in international collaborative research

Informed consent poses challenges in all settings. Challenges may be particularly great in international collaborative research, where cultural perspectives may differ, and where education levels and language may be barriers to participant understanding. We conducted a written survey and focus groups with US health researchers doing research in developing countries, asking about informed consent and other ethical issues in their research. We present here both qualitative and quantitative data relevant to informed consent. Qualitative data revealed that researchers' experiences and beliefs about informed consent fell into three paradigms: regulatory, community, and individual. The regulatory paradigm refers to researchers' views and practices relating to informed consent requirements of institutional review boards and other oversight bodies. The community paradigm refers to researchers' approach to the content and methodology of informed consent in the context of long-term relationships between research teams and study communities. Researchers emphasized the importance of these relationships for creating and maintaining communication fundamental to the informed consent process. Finally, the individual paradigm refers to researchers' views about individual participants' understanding and decision-making process regarding research. Researchers described community-level influences on participants' decision-making, but stressed the need for individual comprehension and voluntary participation. While these paradigms are distinct, they also are intertwined. Quantitative data supported the existence of these three paradigms in respondents' characterization of informed consent. Researchers frequently stated that legal language on the consent forms was meaningless (52%). Forty-four percent of researchers had consulted with community leaders, and 23% believed the consent process focuses too much on the individual, rather than on family or community. Most researchers (82%) reported that the consent process was an important means of educating participants about the study. Fifty-four percent of researchers believed participants did not understand placebos. Further research is needed to understand how culture and relationships affect research participation, and to provide information and dialogue among researchers, oversight bodies and community representatives about appropriate ways to approach informed consent in international research.     

Pre-randomisation in study designs: getting past the taboo

In October 2006 the Dutch Ministry of Health, Welfare and Sport announced that the use of pre-randomisation in study designs is admissible and not in conflict with the Dutch Medical Research in Human Subjects Act. With pre-randomisation, the conventional sequence of obtaining informed consent followed by randomisation is reversed. According to the original pre-randomisation design (Zelen design), participants are randomised before they are asked to consent; after randomisation, only participants in the experimental group are asked to consent to treatment and effect measurement. In the past, pre-randomisation has seldom been used, and when it was, it was often under the wrong circumstances. Awareness regarding the ethical, legal and methodological objections to pre-randomisation is increasing. About a decade ago, we illustrated the applicability and acceptability of pre-randomisation by means of a fictitious heroin provision trial. In general, pre-randomisation is justified if valid evaluation of the effects of an intervention is impossible using a conventional randomised design, e.g., if knowledge of the intervention may lead to non-compliance or drop-out in the control group, or when the intervention is an educational programme. Other requirements for pre-randomisation include the following: the study has a clinically relevant objective, it is likely that the study will lead to important new insights, the informed consent procedure bears no potential harm to participants, at least standard care is offered to participants in the control group, and the approval of an independent research ethics committee is obtained.     

Beyond the informed consent procedure: continuing consent in human research

An ethnographic field study about informed consent in hepatitis C clinical trials provides insight into how changes in protocol requirements and patient health status triggered the actions and decisions of researchers and human subjects during the conduct of these trials. U.S. federal guidelines recommend that informed consent should be conceptualized as more than a one-time event. Rather, a process of continuing consent should be the standard but little is understood about how exactly this process should unfold. We used a proposed typology of continuing consent to frame our analysis and were able to document that only some of the proposed types took place at the site of our study. The most frequent practice involved the researchers' re-consent of their subjects for major protocol revisions. Only one subject dissented and chose to withdraw even though he was technically eligible to continue in the study. Two other types of continuing consent were not observed. We discovered an additional type of continuing consent not described in the typology whereby subjects gave implied consent through their cooperation and adherence to the on-going requirements of the protocols. Implications for the informed consent process and the need for further research are presented.     

Collecting stories: is it research? Is it good research? Preliminary guidance based on a Delphi study

Context  The use of narratives (stories) in research, education, audit and evaluation is increasingly common, but there is no consensus on when research ethics committee approval is necessary for such studies or what counts as 'good narrative research'.
Objective  This study aimed to produce preliminary guidance for researchers, reviewers and ethics committees on what to classify as narrative research in health care and how to evaluate it.
Methods  We carried out a 3-round Delphi study on a volunteer sample of 20 academic researchers, practitioners and service users who were active in narrative health research and its application. After reading academic papers on narrative theory and method, and via extensive online discussion, participants generated a set of preliminary statements. Each participant ranked these on a 9-point Likert scale for relevance and validity (round 1), and then received feedback on his or her scorings compared with the group median and range for each item. This cycle of group discussion, revision of statements, individual rankings and aggregation of scores was repeated twice.
Results  The study produced a definition of narrative research which allows such work to be distinguished from the non-research use of stories in health care, and preliminary quality standards for evaluating narrative research. Most participants on this heterogeneous panel felt able to sign up to the final guidance. Residual disagreements were generally attributable to incommensurabilities in philosophical positions.
Conclusions  Research ethics committees and scientific reviewers may find the guiding principles in this paper a useful starting point for further reflection and discussion about narrative research studies.     

Informed consent in China: quality of information provided to participants in a research project

AIMS: A study was carried out of informed consent strategies in an epidemiological project approved by the regional research ethics committees in Sweden and China and conducted in three areas south-west of Shanghai. METHODS: All participants in the epidemiological project (EP) were included in the research ethical study (RES), which was conducted as a questionnaire-based interview survey in the three areas. Answers were collected by five field interviewers. RESULTS: All participants included answered the questionnaire. Almost all perceived the information provided as rather good or quite good. However, a majority (on average 76%) had the impression that the EP was part of routine healthcare measures, and not a research project. Almost all participants felt free to abstain from participation although 38% in area II stated that they had not been informed about freedom to abstain from participation. A large proportion of participants did not fully understand the nature of the EP. However, almost all participants stated that they would agree to participate in a similar study in the future. CONCLUSION: Although informed consent procedures are supposed to be internationally applicable our study illustrates that it is not always easy to convey information and obtain consent in the present study setting.