Challenges related to informed consent have plagued clinical trials in critical care because patients are acutely ill, study interventions must be delivered quickly, and appropriate decision-makers are often unavailable in the necessary timeframe. Importantly, regulatory provisions in most countries exist that allow research to occur in this context without prospective consent (1). In European Union countries, these regulations typically use a deferred consent model. U.S. regulations permit an exception from informed consent (EFIC) for clinical trials in emergency settings that meet certain criteria (2,3). The most notable difference between deferred consent and EFIC regulations is that deferred consent requires consent for inclusion of an individual’s data in the study, whereas EFIC regulations permit inclusion of data until the point that an individual declines consent or withdraws. Together, these regulations have permitted successful conduct of important clinical trials, but they remain unfamiliar to many investigators, clinicians, and patients. Ethical sensitivity surrounding these studies is also common, and there remains a relatively small body of literature regarding the views of individuals actually included in these studies (4).

The study by van der Wal et al (5) in this issue of Critical Care Medicine contributes importantly to the field of acute care clinical trials. Investigators integrated an assessment of patients’ views of being included in the ICONIC trial, a randomized trial of oxygen targets in mechanically ventilated patients in Dutch ICUs that used a deferred consent approach (6). Specifically, they assessed patients’ perspectives on enrollment in ICONIC 6 months after enrollment, at the same time as they assessed patients’ quality of life (QoL) (5). As reported, the rate of dissatisfaction with enrollment in ICONIC without being able to give consent was very low. Only one patient reported being dissatisfied with enrollment, and 86% were either satisfied/content or neutral. Although acceptance was high overall, the authors also report increasing levels of acceptance of enrollment without consent among individuals who had higher QoL (scored using EQ-5) at 6 months. Notably, the authors report that recollection of participation in the ICONIC trial was low (41% overall).

Overall, these data on acceptance of enrollment in an acute care trial without prospective consent are consistent with other published data. These include data from trials in traumatic brain injury, diabetes control, and status epilepticus, for example, that have been conducted in other countries (7–9). Similarly, the positive association between better outcomes and acceptance has been suggested in a traumatic brain injury population, but these relationships have been less well-studied (10). In this respect, these data are largely concordant with and bolster the current evidence base. There are several findings and implications that are important to highlight.

As the authors note, a distinctive aspect of the ICONIC trial is that it may be viewed as relatively “low risk,” primarily because it randomized patients to oxygen targets within standard practice. In this regard, it may be viewed as very different, for example, from a placebo-controlled trial of a novel agent or a trial of a medical versus procedural intervention. However, this does not minimize the value of data on patients’ perspectives on consent in these types of trials, especially because risk assessment and approach to consent in acute care trials testing standard of care interventions have been controversial (11). Although there are strong arguments that trials such as ICONIC add few risks, they still assess “high stakes” endpoints such as mortality and major morbidity, and there is no settled approach to risk assessment or consent in these kinds of comparative effectiveness trials despite wide recognition that such studies are very important to do. In this regard, this report adds to data from other comparative effectiveness trials suggesting relatively high rates of acceptance of enrollment without prospective consent on the part of many patients when doing so is impracticable, though these data do not challenge the notion that we should try to involve patients and families in enrollment decisions prospectively when that is possible (7,12).

The finding that recall of enrollment was low is also consistent with other published reports of acute care trials. In the context of trials conducted in acute stroke and myocardial infarction, for example, recall of enrollment was low even when prospective consent was obtained (13). In the study reported here, all participants went through a deferred consent process (either the patient or a surrogate), and the survey instrument contained a relatively detailed description of the trial that one would expect to trigger any recollection individuals may have of participation. Yet, only 41% of participants recalled being enrolled. Collectively, these data highlight that a large number of patients and families are not aware of having been enrolled in acute care trials. This trend does not undermine their initial consent. However, it suggests an opportunity to develop strategies for improving postenrollment communication. Enhancing patients’ understanding of studies in which they have been included may increase the extent to which they recognize they have been a part of generating knowledge and may enhance trustworthiness, help to normalize research and communicate the importance to patients and the public of integrating clinical trials into care delivery. Robust communication with patients and families may also enhance the extent to which they feel respected, which is especially important for individuals who may have concerns, and it could facilitate adherence and retention in studies that require more involved follow-up.

Although this study adds to the body of literature in the ways described above, three limitations are notable. First, the deferred consent mechanism itself may introduce selection bias. Anyone who did not consent (either patient or surrogate) to participation in the parent trial (ICONIC) was excluded from the trial and, by extension, this follow-up study. This is a common limitation in studies of consent experiences, but it is especially significant in a study assessing attitudes to enrollment without consent. In this case, 125 of 882 patients (14%) initially randomized into ICONIC were excluded from the trial because they never provided consent. It is unknown what the views of this population are, and no characteristics of these patients are reported, but the reported acceptance in this study is likely an overestimate. Perhaps more important than the implications for understanding acceptance, the exclusion of this number of patients who were initially enrolled and randomized illustrates a challenge with the deferred consent paradigm itself. This is in contrast to the EFIC approach, in which patients must actively decline consent for ongoing participation to be excluded, and data are included (regardless of ongoing consent) up to the point of withdrawal. The second limitation is that acceptance and QoL were assessed at a late time point, 6 months postenrollment. Especially given that recall of enrollment was very low, it is unclear whether patients’ responses reflect constructed views of the study at the time of the survey or recalled views of the experience of enrollment. The relationship between QoL and acceptance is also difficult to contextualize for the same reason. This does not mean the data are not valuable, but it is important to contextualize. A final limitation is that the study did not tease apart views of inclusion from views of consent. The questionnaire did ask whether the participant would have made the same decision initially is able to decide at the time, but it is important to note that responses can differ when patients are asked about their attitudes toward inclusion in general versus being asked specific questions about the absence of consent (14).

In summary, this study, contextualized within prior data, contributes to an important, under-studied area and has some key implications for the critical care trial community. First, acceptance is generally high among patients in appropriately selected studies using alternatives to prospective informed consent. These trials are important and ethical to do, and patients’ reactions are consistent with this. Of course, this does not mean nobody will object to their enrollment, and the threshold of objection that should generate concern is not settled (15). These data also do not reduce the importance of engaging patients and surrogates in enrollment decisions when possible. A consistent theme is that people value opportunities to participate in decisions, even when full informed consent is not achievable (9,13). Second, we should work to understand how to communicate most effectively with patients and families after enrollment has occurred to demonstrate trustworthiness and to ensure people understand their involvement and feel respected and engaged. This is particularly important in settings where mistrust or distrust of healthcare and research is prevalent. Finally, this study shows the value of integrating studies of patients’ and families’ experiences into acute care trials. Just as well-designed trials help to make care better, embedded studies like these can help to make trials better.

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