The ethical analysis of risk in intensive care unit research

Research in the intensive care unit (ICU) is commonly thought to pose 'serious risk' to study participants. This perception may be at the root of a variety of impediments to the conduct of clinical trials in the ICU setting. Component analysis offers a promising approach to the ethical analysis of ICU research. Because clinical trials commonly involve a mixture of study interventions, therapeutic and nontherapeutic procedures must be analyzed separately. Therapeutic procedures must meet the requirement of clinical equipoise. Risks associated with nontherapeutic procedures must be minimized consistent with sound scientific design, and be deemed reasonable in relation to the knowledge to be gained. When research involves a vulnerable population, such as adults incapable of providing informed consent, nontherapeutic risks are limited to a minor increase over minimal risk. Understood in this way, the incremental risk posed by participation in ICU research may be minimal. This realization has important implications for review by institutional review boards of such research and for the informed consent process.     

The ethical analysis of risk in intensive care unit research

Research in the intensive care unit (ICU) is commonly thought to pose 'serious risk' to study participants. This perception may be at the root of a variety of impediments to the conduct of clinical trials in the ICU setting. Component analysis offers a promising approach to the ethical analysis of ICU research. Because clinical trials commonly involve a mixture of study interventions, therapeutic and nontherapeutic procedures must be analyzed separately. Therapeutic procedures must meet the requirement of clinical equipoise. Risks associated with nontherapeutic procedures must be minimized consistent with sound scientific design, and be deemed reasonable in relation to the knowledge to be gained. When research involves a vulnerable population, such as adults incapable of providing informed consent, nontherapeutic risks are limited to a minor increase over minimal risk. Understood in this way, the incremental risk posed by participation in ICU research may be minimal. This realization has important implications for review by institutional review boards of such research and for the informed consent process.     

Risk in Emergency Research Using a Waiver of/Exception from Consent: Implications of a Structured Approach for Institutional Review Board Review

Objective: To apply component analysis, a structured approach to the ethical analysis of risks and potential benefits in research, to published emergency research using a waiver of/exception from informed consent. The hypothesis was that component analysis could be used with a high degree of interrater reliability, and that the vast majority of emergency research would comply with a minimal‐risk threshold. Methods: A Medline search and manual search were done to identify studies using a waiver of/exception from informed consent published between July 1996 and December 2000. A review panel of physicians and bioethicists independently classified nontherapeutic procedures in each study as minimal risk, probably minimal risk, or probably more than minimal risk. Results: Seventy studies using a waiver of/exception from informed consent were identified. A majority of reviewers classified nontherapeutic procedures in 62 studies (88.6%) as minimal risk. Reviewers classified nontherapeutic procedures in six studies (8.6%) as minimal risk or probably minimal risk. In two studies (2.9%), nontherapeutic procedures were classified as probably more than minimal risk. The intraclass correlation coefficient was 0.89 (95% CI = 0.85 to 0.93), indicating very high interrater reliability. Conclusions: Component analysis can be used with high reliability to review emergency research and may improve the consistency of institutional review board review of emergency research. The vast majority of published emergency research performed using a waiver of/exception from consent complies with a properly‐applied minimal‐risk threshold. A minimal‐risk threshold for nontherapeutic procedures protects subjects better than current U.S. regulations while permitting important emergency research to continue.     

Lessons from everyday lives: a moral justification for acute care research

Progress in emergency and critical care requires that clinical research be performed on patients who are incapable of granting consent for research participation. Analyses of the ethics of such research have left some questions incompletely answered. Why should we be permitted to expose vulnerable patients to research risks without their consent? In particular, how do we justify research interventions that have no potential benefit for participants (nontherapeutic interventions)? This article presents a moral justification for nontherapeutic interventions in emergency research. By relying on a framework for assessing research risks, and by drawing on the example of pediatric research, this justification is founded in how institutional review boards, and society in general, analyze risk. Our justification for emergency research also suggests additional protections for emergency research participants, including a stringent threshold for research risk, that still permit important research to proceed.     

Informed consent in the intensive care unit: ensuring understanding in a complex environment

PURPOSE OF REVIEW: Informed consent in the intensive care unit continues to receive marked attention. As greater numbers of patients enter into the intensive care unit with devastating illness, patients and families are faced with more complex medical problems and decisions regarding therapy. Furthermore, research investigations of critical illness add a level of complexity to informed consent and decision making that mandates a careful approach. RECENT FINDINGS: Publications in the past year evidence the potential obstacles for appropriate informed consent. Physicians demonstrate variability in interpretation for the need for informed consent and frequently lack formal training in communicating informed consent. Critical care researchers must communicate the goals and benefits of trial participation carefully, avoiding the demonstrably common pitfall of therapeutic misconception. Excellent consensus statements now exist to guide the researcher in pursuing critical care research, creating informed consent documentation, and recognizing the appropriate setting for waiver of consent. As expected, extended discussion is the most effective tool for improving the quality of informed consent. SUMMARY: Quality of informed consent for the critically ill improves as attention is paid to standardizing indications and formalizing training for physicians. In research, conflicts of interest should be recognized and used to guide the investigator's dialogue on research benefits and risks. Patient safety must be maintained as the primary priority; however, waiver of consent may be considered in situations in which the benefit to medical knowledge far exceeds patient risk.     

Limitations of informed consent for in utero gene transfer research: implications for investigators and institutional review boards

Only 10 years after the first human gene transfer protocols were approved for adults and children, researchers have begun to consider gene transfer on the fetus. While preliminary animal research is ongoing, the enthusiasm and pace of research in this area suggest that human protocols for in utero gene transfer research may be seriously considered in the foreseeable future. Federal guidelines for fetal research rely on minimizing risk and informed consent to protect the "rights and welfare" of both the fetus and pregnant woman. However, in utero gene transfer research poses special challenges to informed consent. This research represents an innovative approach for very ill subjects and takes place in the prenatal setting. These features may converge to undermine the expectant parents' comprehension of, and voluntariness for participation in, research. In this case, informed consent may not be able to bear the weight of adequately protecting the fetus from undue research risks. To compensate for this limitation, and using the regulations for pediatric research as a guide, a greater emphasis should be placed on the benefit/harm assessment rather than informed consent. Selecting diseases/patients where good alternative treatments exist may maximize informed consent, yet this may be a trade-off that exposes the fetus to greater relative risks. On the other hand, selecting diseases/patients without good alternative treatments to prolong life may convey an overestimation of the potential benefits of these interventions, and although care should be taken to strive to improve understanding of these limitations, misunderstanding may persist. However, selecting diseases/patients with no good alternatives might make serious risks more tolerable, and this should take precedence over informed consent. The limitations of informed consent brought into focus by the special features of in utero gene transfer research may be relevant to a broader range of innovative investigations.     

European legislation impedes critical care research and fails to protect patients' rights

The European Clinical Trials Directive requires an informed consent from the patient or a proxy in drug trials. Although informed consent is a valuable tool to protect patients' rights in clinical trials, this requirement largely impedes research in critical care settings, and if pursued in this context, it does not provide the patient with adequate protection. Instead of insisting on informed consent, we suggest that the focus should be shifted towards two other ethically relevant elements in human experimentation: risk assessment and selection of research subjects. When reviewing protocols in which a waiver of consent is deemed necessary, the Ethical Review Board should ensure that non-therapeutic risks are minimal, that the research is specifically designed to benefit critically ill patients, and that it cannot be conducted under circumstances where an informed consent can be obtained. If the European Directive is changed accordingly, this permits clinical trials in critical care settings, while adequate protection from risky non-therapeutic procedures is ensured and exploitation of the patient as an easily accessible research subject is prevented.     

Waiver of informed consent: A survey of emergency medicine patients

Changes to Federal regulations pertaining to waiver of informed consent for acute care research were debated by the research and regulatory communities for more than 2 years before being finalized in October of 1996. Input from the general public was limited. This survey investigated the opinions of emergency medicine patients concerning wavier of informed consent for acute care research. A convenience sample of 212 patients were approached at a tertiary care academic urban emergency department. Seventy-three percent approved of waiver of informed consent if the absolute risks were minimal (50% if the absolute risks were greater than minimal but the incremental risk were minimal). Educational status and certain aspects of the patient's current health status (but not age, race, or gender) significantly affected the results. While most emergency medicine patients would want to be enrolled in a study if they had a serious illness and were unable to give informed consent, a significant percentage of patients would not want to be enrolled regardless of the degree of risk or availability of a family member to speak on their behalf. Waiver of informed consent for emergency research is an ethical dilemma pitting individual rights against societal needs and physician parentalism. A better understanding of what patients consider appropriate may help in resolving this dilemma.     

Evaluating the quality of information about alternatives to research participation in oncology consent forms

A careful consideration of the alternatives to research participation is an essential element of making an informed choice to enroll in a biomedical research study. While there is general agreement on the importance of informing prospective subjects about alternatives to research participation, little is known about how investigators communicate this information. The purpose of this study was to attempt to assess the quality of information about alternatives contained in informed consent documents in oncology randomized controlled trials. Our study indicates that there is room for improvement concerning the discussion of alternatives to research participation in informed consent documents in oncology randomized controlled trials. Though most of the documents in our study met the minimal disclosure standard found in the U.S. federal regulations, less than a third met the reasonable person standard, a widely accepted principle endorsed by the common law and various ethics guidelines and documents. There was a statistically significant difference between the alternative discussions in local and model forms (P < 0.0014). The alternatives discussions in local informed consent documents were more likely to receive higher scores than those in model consent documents, with an odds-ratio of 3.5 to 1.     

Balancing the needs of the scientist and the subject in trauma research

All participants in research are vulnerable to some extent. Survivors of trauma are often sought as participants for research studies and may be at an increased risk of emotional or psychological distress as a result of research participation. Scientists need to pay careful attention to issues of informed consent and the potential harm and benefits from research participation. This article explores challenges of selecting a sample, informed consent, and study continuation when conducting research with survivors of trauma.     

Doing research on the ethics of doing research

In the previous issue of Critical Care Chenaud and colleagues found that most intensive care unit patients who had given informed consent for their participation in a clinical trial could not recall either the purpose of the trial or its related risks several days later. These findings should remind us that informed consent is a process, not an event, but they should not be interpreted to mean that recall is, of itself, a useful criterion for evaluating either the validity or the quality of the informed consent process. On an entirely separate note, the decision of the authors not to obtain informed consent for this study itself raises interesting questions about the ethics of doing research on the ethics of doing research.     

Impact of detailed informed consent on research subjects' participation: a prospective, randomized trial

This study was undertaken to measure potential research subjects' participation in a survey research design, based on level and type of informed consent required before enrollment. In this prospective, randomized trial, 300 eligible Emergency Department participants were randomized to one of three groups: verbal consent (n = 100), limited written consent (n = 100), and detailed written consent with signature (n = 100). The consent was related to a self-administered patient satisfaction survey. The primary outcome was level of participation, where participation was categorized as full, limited, or refusal. Ninety-five percent confidence intervals (CI) constructed about proportions were used to assess differences in participation rates between the three consent groups. Among 300 participants, no demographic differences were found between groups for age or gender. Participants who were randomized to complete the detailed written consent had a significantly lower rate of full participation (72%) when compared to those randomized to verbal consent (85%; mean difference between groups 13%, 95% CI 2% to 24%) and to those with limited written consent (84%; mean difference between groups 12%, 95% CI 1% to 23%). Participants randomized to detailed written consent also had a significantly higher refusal rate (23%) when compared to those in the limited written group (12%; mean difference between groups -11%, 95% CI -21% to -1%). The length and type of informed consent required affected potential research subject participation in a survey research design. Participants who were asked to sign a detailed written informed consent document had a lower rate of participation compared to those with verbal or limited written consent.     

Randomized evaluation of trial acceptability by INcentive (RETAIN): Study protocol for two embedded randomized controlled trials

IntroductionThe most common and conceptually sound ethical concerns with financial incentives for research participation are that they may (1) represent undue inducements by blunting peoples' perceptions of research risks, thereby preventing fully informed consent; or (2) represent unjust inducements by encouraging enrollment preferentially among the poor. Neither of these concerns has been shown to manifest in studies testing the effects of incentives on decisions to participate in hypothetical randomized clinical trials (RCTs), but neither has been assessed in real RCTs.Methods and analysesWe are conducting randomized trials of real incentives embedded within two parent RCTs. In each of two trials conducted in parallel, we are randomizing 576 participants to one of three incentive groups. Following preliminary determination of patients' eligibility in the parent RCT, we assess patients' research attitudes, demographic characteristics, perceived research risks, time spent reviewing consent documents, ability to distinguish research from patient care, and comprehension of key trial features. These quantitative assessments will be supplemented by semi-structured interviews for a selected group of participants that more deeply explore patients' motivations for trial participation. The trials are each designed to have adequate power to rule out undue and unjust inducement. We are also exploring potential benefits of incentives, including possible increased attention to research risks and cost-effectiveness.     

Voluntary Informed Consent in Research and Clinical Care: An Update

Informed consent is important: in research, it allows subjects to make an informed and voluntary choice to participate—or refuse to participate—in a project where they will be asked to take risks for the benefit of others. In both research and clinical care, informed consent represents a permission to intervene on a person's private sphere. The elements of informed consent are usually described as disclosure, understanding, decision‐making capacity, and voluntariness. Each poses distinct difficulties, and can be amenable to improvements. However, research on the quality of informed consent and on strategies intended to improve it have only become the object of research relatively recently. In this article, we describe some results of this research, and outline how they can be relevant to informed consent in research and clinical care. Although much of the data suffers from limitations, it does suggest that disclosure has improved, but is still uneven, comprehension is often poor, for both patients and research subjects. Moreover, trust is a motivating factor for research participation, and thus we run risks if we allow false expectations and prove ourselves unworthy of this trust. Although improving consent forms does not have a clear effect on understanding, improving the consent process may help. Finally, better information may decrease anxiety and seems to have at most a small negative effect on research recruitment.     

Consent and assent to participate in research from people with dementia

Conducting research with vulnerable populations involves careful attention to the interests of individuals. Although it is generally understood that informed consent is a necessary prerequisite to research participation, it is less clear how to proceed when potential research participants lack the capacity to provide this informed consent. The rationale for assessing the assent or dissent of vulnerable individuals and obtaining informed consent by authorized representatives is discussed. Practical guidelines for recruitment of and data collection from people in the middle or late stage of dementia are proposed. These guidelines were used by research assistants in a minimal risk study.     

Clinical trials in an emergency setting: implications from the fifth version of the Declaration of Helsinki

Everybody agrees that research is crucial to improve the quality of emergency care. Consent of human subjects for participation in research requires that they fully understand their role and risk, not be coerced, and be allowed to withdraw at any time without penalty. In an emergency situation, informed consent is not always possible but the need for good research data is very high. Here is the ethical difficulty, and a real conflict of values: a population that might ultimately benefit from research cannot consent to the research and are thus excluded from the potential therapeutical advances. Patients at high risk of morbidity or death, with cardiac arrest, shock, head injury, or altered mental status, are evidently incapable of providing an adequate consent, but nevertheless are often in the greatest need of innovative therapy and might be willing to assume some risk for potential benefit. In an attempt to resolve this dilemma, the new version of the Declaration of Helsinki presents updated requirements for the waiver of informed consent and the protection of human subjects in emergency research.     

Ethical challenges in neonatal research: Summary report of the ethics group of the newborn drug development initiative

BACKGROUND: The Newborn Drug Development Initiative (NDDI) was established to address the lack of substantive data supporting efficacy and safety of drugs in the neonate. OBJECTIVE: This commentary summarizes some of the ethical issues involved in neonatal drug development. METHODS: At the NDDI workshop held March 29 and 30, 2004, in Baltimore, Maryland, members of the Ethics Group were dispersed among the subspecialty groups before convening to discuss common ethical themes. The Ethics Group then met together to identify and discuss those ethical themes that were both important and shared among the groups. These themes are discussed and illustrated with the other NDDI group reports. This workshop was cosponsored by the National Institute of Child Health and Human Development and the US Food and Drug Administration. RESULTS: Neonatal drug research is scientifically and ethically necessary to establish the efficacy and safety of drugs widely used in newborn medicine. However, research involving neonates must be carefully designed to balance potential risks and benefits, with consideration given to the component analysis of risk. The protocols proposed by the NDDI groups would be considered greater than minimal risk and offering prospect for direct benefit, thus adhering to the Department of Health and Human Services' pediatric research regulations (Subpart D). The NDDI groups all proposed randomized controlled clinical trials, with careful attention to scientifically and ethically appropriate control groups. Multiple regulatory bodies have affirmed that in the absence of proven effective treatment or when a proven treatment offers marginal benefits, study designs with placebo controls are ethical. Obtaining parental permission is a complex issue, with a paucity of evidence describing the feasibility of informed and voluntary consent under conditions of duress and a short therapeutic window. The Subpart D regulations offer sufficient protection to critically ill neonates. The application of the revised Subpart B regulations would restrict the use of a waiver of consent for minimal risk research and for emergency research, and would not allow research that offers no direct benefit and no more than a minor increase over minimal risk. CONCLUSIONS: Multisite collaboration involving standards of care and institutional review board procedures may be important for establishing scientific and ethical consistency. Ongoing dialogue among researchers, clinicians, parents, and other interested parties is essential to promoting ethically and scientifically sound neonatal clinical research.     

Consent in resuscitation trials: Benefit or harm for patients and society?

CONTEXT: Research in an emergency setting is challenging because there may not be sufficient opportunity or time to obtain informed consent from the patient or their legally authorized representative. Such research can be conducted without prior consent if specific criteria are met. However consent is sometimes required for continued participation and may bias the results of the study. OBJECTIVE: To review regulations related to waiver of consent in emergency research, and evidence of whether such regulations introduce bias. RESULTS: Emergency research can be conducted without consent, either through community disclosure and consultation followed by patient or family notification and consent for continued participation after the intervention was applied, or under a minimal risk waiver. Review of the clinical record is necessary to determine important outcomes such as survival to discharge. If consent is required for this review but not granted, then these data are missing during analysis. If seriously ill or disadvantaged patients are less likely to assent, then investigators cannot determine reliably whether these vulnerable patients were harmed by the intervention. If missing data are different from complete data, then the analysis is susceptible to bias, and the conclusions could be misleading. Extrapolation from non-consent rates in resuscitation studies to results from the DAVID trial demonstrates that the rate of absence of data and information due to lack of assent can influence whether there is a significant difference between treatment groups (survival of control versus intervention: p=0.04 for complete data; p=0.08 for 10.8% lack of assent; p=0.40 for 19.7% lack of assent). CONCLUSIONS: Exception from consent for emergency research should extend to review of the hospital record as the standard in emergency research. The only potential risk to patients associated with review of the clinical record after the intervention is loss of privacy and confidentiality. Appropriate safeguards can be taken to minimize this risk.     

The requirement for informed consent prior to nursing care procedures

AIM OF THE PAPER: The aim of this paper is to examine the extent to which there is a requirement to obtain informed consent prior to nursing care procedures. RATIONALE: The requirement for nurses to obtain consent prior to nursing care procedures is addressed in various nursing policy documents. It is important that nurses understand the legal and ethical rationale behind the principles of informed consent so that the principles are applied appropriately to the particular context of nursing care. ARGUMENT: The ethical and legal rationale behind the concept of informed consent and its relevance to nursing practice are examined. In this paper, it is argued that the function of informed consent is to protect patient autonomy and to promote meaningful decision-making. Given the potential for nursing care procedures to infringe patient autonomy, consent is clearly a relevant concept in nursing. Furthermore, in law, any touching without consent is a potential battery. Informed consent is often associated as a rigid procedure, only relevant to surgical or research procedures. Consent should be obtained prior to nursing care procedures whenever patient autonomy is at stake. However, information-giving should be determined by the needs of the patient and approached in such a way as to facilitate meaningful decision-making. Given the individual nature of infringements to patient autonomy, it is difficult to predetermine all those care procedures that require consent; any list of procedures would fail to be comprehensive. CONCLUSIONS: The principles of informed consent should underpin our approach to nursing care procedures, which should not be mechanistic but determined by the needs of individual patients.     

Ethical assessment of pediatric research protocols

Specific regulations regarding oversight of research in children vary from country to country, but most share common principles derived from major consensus documents. Whereas the permissibility of research on adults depends heavily upon the informed consent of the subject, the regulation of research in pediatrics is focused primarily upon protection of the subjects from research risks. Since patients who require intensive care are commonly at high risk for complications related to the severity of their illnesses, justifying the risks of research on critically ill children may therefore be particularly challenging. Use of an approach known as “component analysis” can be very helpful in separating the risks attributable to the medical care itself from those that should be ascribed to the research. After identifying and isolating the research interventions, a three-step approach is helpful for evaluating the “net risks” of the research: (1) Separate each component of the research into discrete interventions. (2) Any intervention for which the benefits equal or exceed the risks is ethically justified. (3) For interventions in which the risks exceed the benefits, the “net risk” for each intervention needs to be justified, as follows: (a) the interventions may not exceed the locally defined threshold for pediatric research (e. g., not greater than a minor increment more than minimal risk, as in the U.S. regulations); and (b) the scientific value of the study for improving the care of future children must be sufficient to justify the sum of the net risks of the research interventions.