'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.     

Alternatives for randomization in lifestyle intervention studies in cancer patients were not better than conventional randomization

ObjectiveAssessing effects of lifestyle interventions in cancer patients has some specific challenges. Although randomization is urgently needed for evidence-based knowledge, sometimes it is difficult to apply conventional randomization (i.e., consent preceding randomization and intervention) in daily settings. Randomization before seeking consent was proposed by Zelen, and additional modifications were proposed since. We discuss four alternatives for conventional randomization: single and double randomized consent design, two-stage randomized consent design, and the design with consent to postponed information.Study Design and SettingWe considered these designs when designing a study to assess the impact of physical activity on cancer-related fatigue and quality of life. We tested the modified Zelen design with consent to postponed information in a pilot. The design was chosen to prevent drop out of participants in the control group because of disappointment about the allocation.ResultsThe result was a low overall participation rate most likely because of perceived lack of information by eligible patients and a relatively high dropout in the intervention group.ConclusionWe conclude that the alternatives were not better than conventional randomization.     

The validity and ethics of giving placebo in a randomized nonpharmacologic trial was evaluated

OBJECTIVE: When studying the effects of a non-pharmacologic intervention, the choice of a control group is often difficult. In a study on the effectiveness of increased water intake on voiding dysfunction in elderly men we used an unusual design. This article addresses the internal validty and ethics of this design. STUDY DESIGN AND SETTING: The randomized trial we evaluated had a 6-month follow-up period and was carried out among 141 elderly men with moderate lower urinary tract symptoms. The experimental group was given the instruction to drink more water, the control group received placebo medication. The participants were not informed that there was a 50% chance of receiving placebo. We measured whether the prior expectations and preferences were comparable for the two study groups, whether blinding was preserved throughout the study period, and whether the participants considered this design ethical. RESULTS: Prior to randomization, patients had higher expectations for the experimental intervention, but there was not statistically significant difference in their preference. During the study period, two out of 71 patients in the control group unmasked the placebo. In general, both groups fully agreed with the informed consent procedure. CONCLUSION: This design can be considered when the effects of a non-pharmacologic interventions are studied.     

Adapting the randomized consent (Zelen) design for trials of behavioural interventions for chronic disease: feasibility study

OBJECTIVES: Standard randomized controlled trials of interventions for chronic conditions that involve behavioural change, or that are highly desired by participants, are difficult to undertake because of problems with recruitment and contamination. Alternatives include cluster-randomized trials or pre-randomization designs such as the Zelen design. The aim here was to develop a pre-randomization design that would overcome ethical and methodological problems associated with the conventional Zelen design, and permit the rigorous evaluation of a complex package of care, involving physical therapy and behavioural changes, for patients with painful patello-femoral osteoarthritis of the knee joint. METHODS: Eligible patients were first consented to a one-year observational study of their arthritis. They were subsequently randomized into intervention and control arms. Those in the intervention arm were then asked if they were willing to participate in a further study involving regular sessions with a physiotherapist. Those in the control arm were not told about this, but were followed up as agreed. RESULTS: Eighty-seven patients consented to the observational study, 43 of whom were subsequently randomized to the intervention arm. All 43 consented to the intervention, although five of these did not receive the full package of care. Assessments were carried out at five months and one year on 82 patients, and concealment was satisfactorily maintained in the majority. CONCLUSIONS: We conclude that this study design could potentially offer an acceptable compromise between the need for scientific rigour and the ethical imperative of fully informed consent in trials that involve behavioural change or interventions that patients might want to obtain.     

The stepped wedge design

Not all questions concerning therapeutic effects in medical research can be answered satisfactorily by standard trials. The stepped wedge cluster design is a special form of randomised study in which an intervention at group level is implemented in stages. The design can be used in situations where randomization at the patient level is inappropriate or impossible and where a stepped implementation of the experimental intervention is important for ethical, logistic or financial reasons. The time before the experimental intervention is introduced in a cluster is used as control period. The statistical analysis of cluster trials should account for the fact that individuals within clusters may show many similarities. Ethical aspects of stepped wedge design should be considered carefully, especially when obtaining individual informed consent is not possible.     

Reasons why patients do or do not participate in clinical trials; a systemic review of the literature

OBJECTIVE: To assess the factors that may influence a patient's consent to participate in a clinical trial. DESIGN: Systematic literature survey. METHOD: Studies on the characteristics of patients, trials, the physicians requesting informed consent and the informed consent procedures were looked for in Medline, Embase, and Cinahl. Articles published in English, German, Dutch or French in the period 1980-2002 and originating in Europe, the United States, Canada, New Zealand or Australia were included. Studies on non-adults, healthy experimental subjects or less than 30 patients were excluded. RESULTS: Thirty suitable studies were retrieved. Factors that may affect the granting of consent to participate in a clinical trial included: uncertainty of the patient, randomisation and the use of a placebo, the relationship between the person asking for informed consent and the patient, and the dissemination of information during the informed consent procedure. Since these factors are often interrelated, no single factor could be identified as decisive for participation in a clinical trial; they can influence the decision of the patient to participate in a trial in either a positive or a negative direction. CONCLUSION: Optimalization of the information concerning informed consent, the way the information is provided and the attitude of the person requesting informed consent are important and sometimes decisive factors that may determine the participation process.     

Ethics of medical scientific research: informed consent and the therapeutic misconception

--Ethical approval of research involving human beings is based on two pillars: supervision of the scientific merit of the research and the risks and burdens for participants by an institutional review board (IRB) or the Dutch Central Committee on Research Involving Human Subjects (CCMO), and obtaining informed consent from the participant or his or her legal guardian. --Discussions on the ethical acceptability of a study generally focus on the first pillar, assessment by an IRB. The second pillar, obtaining informed consent, is often neglected. --Some ethical concepts play a role in obtaining informed consent, especially the concept of the 'therapeutic misconception', i.e. that participating in a study is the same as receiving individualised treatment from a physician. --Of importantance in this matter is the fundamental difference between the research relationship (between investigator and participant) and treatment relationship (between physician and patient). --Understanding the concept of therapeutic misconception is essential to explaining why it is often difficult to obtain valid informed consent from patients for medical research.     

It's not just what you say,it's also how you say it: Opening the ‘black box’ of informed consent appointments in randomised controlled trials

Randomised controlled trials (RCTs) represent the gold standard methodology for determining effectiveness of healthcare interventions. Poor recruitment to RCTs can threaten external validity and waste resources. An inherent tension exists between safeguarding informed decision-making by participants and maximising numbers enrolled. This study investigated what occurs during informed consent appointments in an ongoing multi-centre RCT in the UK. Objectives were to investigate: 1] how study staff presented study information to participants; 2] what evidence emerged as to how well-informed participants were when proceeding to randomisation or treatment selection; and 3] what aspects of the communication process may facilitate improvements in providing evidence of informed consent. Qualitative analysis of a purposive sample of 23 recruitment appointments from three study centres and involving several recruitment staff applied techniques of thematic, content and conversation analysis (CA). Thematic analysis and CA revealed variation in appointment content and structure. Appointments were mostly recruiter-led or participant-led, and this structure was associated with what evidence emerged as to how participants understood information provided and whether they were in equipoise. Participant-led appointments provided this evidence more consistently. Detailed CA identified communication techniques which, when employed by recruiters, provided evidence as to how participants understood the choices before them. Strategic use of open questions, pauses and ceding the floor in the interaction facilitated detailed and systematic exploration of each participant's concerns and position regarding equipoise. We conclude that the current focus on content to be provided to achieve informed consent should be broadened to encompass consideration of how information is best conveyed to potential participants. A model of tailored information provision using the communication techniques identified and centred on eliciting and addressing participants' concerns is proposed. Use of these techniques is necessary to make potential participants' understanding of key issues and their position regarding equipoise explicit in order to facilitate truly informed consent.     

Record linkage research and informed consent: who consents?

Background  

Linking computerized health insurance records with routinely collected survey data is becoming increasingly popular in health services research. However, if consent is not universal, the requirement of written informed consent may introduce a number of research biases. The participants of a national health survey in Taiwan were asked to have their questionnaire results linked to their national health insurance records. This study compares those who consented with those who refused.     

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.     

The influence of informed consent content on study participants' contraceptive knowledge and concerns

Little is known about how the information presented in the informed consent process influences study outcomes among participants. This study examines the influence of informed consent content on reported baseline contraceptive knowledge and concerns among two groups of HIV-serodiscordant and seroconcordant HIV-positive couples enrolled in research projects at an HIV research center in Lusaka, Zambia. We found significant differences in the reporting of contraceptive knowledge and concerns between couples viewing consent materials that included detailed information about contraception and those viewing consent materials that lacked the detailed information. We conclude that the design of informed consent materials should strike a balance between ensuring that participants give truly informed consent and educating participants in ways that do not compromise the assessment of the impact of behavioral interventions.     

A qualitative study of subject recruitment for familial cancer research

PURPOSE: Familial epidemiological studies of cancer raise familiar ethical issues relating to informed consent and recruitment of participants. When the family is the unit of study, however, additional complexity arises. Educating and recruiting participants must be tailored to the relatives', as well as the proband's needs. An understanding of the prospective participants' concerns will aid the development of strategies for recruitment and will facilitate informed and voluntary consent. In the present study, qualitative methods were used to investigate these issues. METHODS: Focus groups with cancer patients, relatives of cancer patients, and individuals from the general population were separately conducted to identify issues that concern people who are asked to participate in family studies. RESULTS: Many of the issues which arose in the course of the focus group discussions were similar to those in any study. Yet, some of the themes emerging from the discussions were specific to familial research. In particular, participants expressed that the study should be endorsed by a trusted and familiar source; group discussions might facilitate the consent process; the benefit of the research should be clear and personal, as well as benefit the participants' family members; risks of participation should be explicit (e.g., insurance discrimination); and education about the disease and its familial nature would maintain commitment to the study. Finally, participants expressed concerns about being approached by programs to facilitate the identification and recruitment of other family members for research on family health issues. CONCLUSIONS: Findings from this study will aid future familial studies in developing a protocol that both adequately informs potential participants of the nature of familial research and maximize participation.     

Deferred consent for inclusion of patients unable to give their consent in studies in the field of emergency medicine

Respect for individual autonomy, expressed in the concept of informed consent, is a basic principle in research with humans. Many patients in intensive care are unable to give consent because of mental incapacity, and this can be further complicated in emergency research, in which the treatment or experiment needs to be initiated without delay. In those situations consent can be deferred. Randomization is done without prior consent, followed by patients' or relatives' consent at a later stage. Butwhat should one do with the data if the patient dies at an early stage after randomization before consent could be obtained? Should the data be used or not? Should the relatives be asked for consent for using the data? The Dutch Central Committee on Research involving Human Subjects (CCMO) states that asking for consent after the patient has died makes no sense, because with the death of the patient the research has ended. Relatives do not have the authority to give consent for the use of medical data after the patient has died. Data can be used anonymously in the final analysis of the trial. We propose a flowchart for this procedure.     

Telehealth in cystic fibrosis: a systematic review

We conducted a systematic review of the use of telehealth in people with Cystic Fibrosis (CF). The studies reviewed were of adults and children with CF, and incorporated telehealth for monitoring symptoms, assessing adherence to prescribed therapies or providing a therapeutic intervention. Searches of four electronic databases returned 293 references. Eight studies met the inclusion criteria. Variability in study design and outcome measures precluded meta-analysis. Seven studies assessed telemonitoring feasibility for patient usability and acceptance, or for physiological monitoring. Two studies were randomised controlled trials, although only one showed differences in outcome between the intervention and usual care with improved spirometry stability and significantly increased antibiotic use in the intervention group. In four studies participants were asked to transmit data on spirometry (FEV(1)) or symptoms. Participant non-compliance with data reporting ranged from 43-63%. Generally, participants reported being able to use the required technology. There is insufficient evidence to reach a firm conclusion about the benefits of telehealth in people with CF, but it remains a promising area for future investigation.     

Patient preferences in randomised trials: threat or opportunity?

OBJECTIVES: To assess whether it is feasible to elicit patients' preferences for treatments and then to proceed with randomisation which may allocate those with preferences to their less preferred treatment; and to describe which prognostic variables were associated with such preferences within the context of a randomised trial of an exercise programme for back pain. METHODS: The first 97 patients enrolled in a randomised controlled trial (RCT) for the treatment of back pain were asked about their preferences, health characteristics and other prognostic variables. RESULTS: Fifty-eight (60%) patients preferred to be allocated to the exercise programme whilst 38 (39%) were indifferent; one patient preferred conventional general practitioner (GP) management. No patient refused randomisation. Comparing patients preferring the exercise programme with indifferent patients showed that the former had a higher belief in the effectiveness of the new treatment (P < 0.01), tended to have worse back pain (P = 0.09), had back pain for a shorter duration (P = 0.04), and tended to have had more GP home visits (P = 0.06). CONCLUSIONS: For many randomised trials preference may be an important prognostic variable. In such circumstances, preference should be taken into account in the final analysis. This study demonstrates it is sometimes feasible to randomise patients to their less preferred treatment, thus allowing more robust statistical comparisons between randomised groups. This modification may make RCTs more rigorous and improve their external validity.     

医疗紧急情况下知情同意的代理相关法律问题

传统的知情同意原假设是,如果病人没有充分的自主,医疗干预便不能实施,医师在知情同意中的重心是建议者而非治疗者的角色。但是在医疗紧急情况下,本着生命优先、救死扶伤的原则,知情同意严格程序形式需要作出让步,病人的昏迷状态或者濒危状态使得其无法具有自主的能力,就需要通过代理实现同意功能的延伸。紧急情况下将会遇到的非本人的其他主体能否代理、有无能力代理、会否滥用代理权等一系列相关的法律问题。     

Informed well-considered consent ('informed consent'): an end or a means?]

Since World War II, all sorts of protective measures have been taken for people who receive medical care or who are involved in scientific research. More and more, informed consent has become the standard. In the field of experimental therapeutical research, informed consent is still a controversial subject; the individual person's interests versus general interests. But informed consent appears to have become such an absolute prerequisite for all types of observational research that the future of epidemiological research based on existing data is threatened. According to both the Declaration of Helsinki and the Dutch Law for Protection of Persons, it is possible to omit asking individual informed consent under certain circumstances. Permission for research could then be given by a supervisory board or a medical-ethical commission. After all, informed consent was never meant to be a goal of its own, but a means for self-protection and securing the right to autonomy. In situations where this right is curbed for other reasons, it appears that insisting on informed consent misses its target completely.     

Supervision of medical scientific research with mentally competent subjects is impossible without reviewing

The object of reviewing medical scientific research in humans is to offer guarantees against, especially, violations of physical integrity and privacy. Since the scientific interest is a matter of first importance, the research has to be checked for its reasonableness and for the test subject's consent. Omission of these checks in case the risk or stress to be expected is slight is contrary to these criteria. Reversion of the sequence of informed consent and randomization is contrary to the requirement of consent. Free, informed consent may be assumed if in a trial with a control group the test subject is informed beforehand about the study design and the risks, but is not told if he is to receive a standard therapy, a placebo or a test medication.     

Development of a complex intervention improved randomization and informed consent in a randomized controlled trial

ObjectiveMulticenter randomized trials are required for pragmatic evaluations of health care interventions, but recruitment is difficult. Systematic reviews failed to identify robust strategies to improve recruitment. We developed and evaluated a complex intervention to increase levels of randomization and informed consent.Study Design and SettingThe ProtecT (Prostate testing for cancer and Treatment) trial compares radical surgery, radical conformal radiotherapy, and active monitoring for men aged 50–69 years with localized prostate cancer. The intervention was developed using qualitative research methods (content, thematic and conversation analysis). Rates of randomization and immediate acceptance of allocation were measured every 6 months to evaluate the impact of the intervention.ResultsThe complex intervention comprised reviews of centers falling below study targets, training programmes, documents and individually tailored feedback. Over 65% of eligible participants consented to randomization. Trial participants became increasingly well informed as immediate acceptance of allocation rose from 65% to 81% between 2001 and 2005.ConclusionThis complex intervention resulted in high levels of randomization and informed consent in a difficult trial. The generic aspects of the intervention could be applied to other trials to maximize randomization and informed consent, and allow the mounting of trials previously considered too difficult.