The influence of consent models on recruitment rates in randomised trials in critical care: A systematic review

Consent in critical care trials: a survey of Canadian research ethics boards and critical care researchers

Critical care trials are limited by problems with participant recruitment, and little is known about the most effective ways to enhance trial participation. Despite clinical research improving in the past decades within intensive care, participant recruitment remains a challenge. Not all eligible patients are identified, and opportunities for enrolment into clinical trials are often missed. Interventions to facilitate recruitment need to be identified to improve trial conduct in the critical care environment. Therefore, we aimed to establish the effectiveness of recruitment strategies in critical care trials in order to inform future research practice. Databases including MEDLINE, Embase, CINAHL and PsycINFO were searched for English language papers from inception to February 2020. The objectives were to: (1) establish the effectiveness of recruitment strategies and (2) recommend how effective recruitment strategies can inform research practice. Two reviewers independently assessed papers for inclusion and critically appraised the quality of the studies. Discrepancies were discussed within the research team. Relevant data were extracted and thematically coded into five overarching themes using a narrative synthesis approach. The review was prospectively registered on PROSPERO (CRD42019160519). The search resulted in 2509 initially identified articles, with 15 that met the inclusion criteria. Articles reported a combination of quantitative, mixed methods and qualitative studies and a range of low-, moderate- and high-quality studies. Although, in-keeping with narrative synthesis approaches, none were excluded based on methodological quality. Five themes were identified relating to: patient eligibility identification, who provides information and seeks consent, resource limitations, research culture or environment and the consent model used. The relative success of recruitment strategies was dependent upon the experience and availability of the staff involved in the approach, trial design, the application of the strategy to the specific intensive care environment, the acceptability of the recruitment and consent models used, and the efficiency of the recruitment procedures. Opportunities for consent were missed in a proportion of eligible patients in most studies, suggesting that clinicians may avoid recruiting more complex patients or in more complex situations and that further development of strategies is needed. More effective recruitment strategies are required to enhance recruitment and the representativeness of the patient sample obtained in critical care trials, in order to expand the evidence base for treatments in this field. Greater focus is needed on assessing the performance of different recruitment strategies within different types of studies and critical care research environments. Future research should explore key stakeholders' experiences of, and attitudes towards, recruitment and establish the most important and feasible modifiable barriers to recruitment.

Randomized clinical trials (RCTs) are conducted to guide clinicians' selection of therapies for individual patients. Currently, RCTs in critical care often report an overall mean effect and selected individual subgroups. Yet work in other fields suggests that such reporting practices can be improved. Specifically, this Critical Care Perspective reviews recent work on so-called "heterogeneity of treatment effect" (HTE) by baseline risk and extends that work to examine its applicability to trials of acute respiratory failure and severe sepsis. Because patients in RCTs in critical care medicine-and patients in intensive care units-have wide variability in their risk of death, these patients will have wide variability in the absolute benefit that they can derive from a given therapy. If the side effects of the therapy are not perfectly collinear with the treatment benefits, this will result in HTE, where different patients experience quite different expected benefits of a therapy. We use simulations of RCTs to demonstrate that such HTE could result in apparent paradoxes, including: (1) positive trials of therapies that are beneficial overall but consistently harm or have little benefit to low-risk patients who met enrollment criteria, and (2) overall negative trials of therapies that still consistently benefit high-risk patients. We further show that these results persist even in the presence of causes of death unmodified by the treatment under study. These results have implications for reporting and analyzing RCT data, both to better understand how our therapies work and to improve the bedside applicability of RCTs. We suggest a plan for measurement in future RCTs in the critically ill.

Update in Critical Care for the Nephrologist: Transfusion in Nonhemorrhaging Critically Ill Patients

Clinical trials in critical care are often resource-intense, with many unique challenges. Barriers to effective recruitment and implementation of study intervention have not been explored in a UK context. To identify facilitating factors and barriers to enrolling patients into critical care clinical trials within the UK from clinician's perspectives. A qualitative interview study was undertaken on behalf of the National Institute of Health Research critical care specialty group, in which research active clinicians across different Clinical Research Networks were interviewed. A loosely structured interview schedule was used, based on themes generated from the literature associated with accessing critical care trials. Research teams (critical care doctors, research nurses, and trial coordinators) from hospitals from each Clinical Research Network were contacted to try to achieve representation across the UK. Interviews were carried out across nine UK Clinical Research Networks with a range of doctors and research nurses. All hospitals were teaching hospitals with varying research nurse numbers and allocated consultant research sessions. There were a range of six to nine ongoing clinical trials in critical care for each centre representative interviewed. Data were analysed using framework analysis, and six final themes were identified related to factors associated with: centre, unit, resources, study, clinician, and patient/family. The most commonly cited barrier to conducting clinical trials was related to resources, namely insufficient human and financial resources, leading to staff and study recruitment difficulties. Clinical uncertainty and equipoise regarding comparative merits of trials were challenging in terms of engaging critical care teams. A number of patient and family factors added complexities in terms of recruitment; however, refusal rates were generally reported as low. Flexibility in funding and employment by research teams enables continuity of studies and staff. Innovative measures to incentivise research nurses and clinical teams can help recruit more patients into trials. Research teams are highly committed to providing cover to recruit critical care trials, and a significant effort to anticipate barriers is undertaken; these endeavours are summarised to provide guidance for other teams wishing to address any potential difficulties.

Background Informed consent rates are inconsistently incorporated in trial reports, and literature on consent patterns and predictions is sparse, particularly in the field of critical care. Objective The overall objective of this study is to describe the patterns and predictors of consent rates in REVISE. The specific aims are to analyze the consent models used, consent rates, participants in the consent encounter, reasons for declined consent, and factors associated with obtaining consent. Methods This is a pre-planned secondary study of the REVISE Trial (NCT03374800) which compared pantoprazole to placebo on the outcome of clinically important upper gastrointestinal bleeding among invasively ventilated patients in the intensive care unit (ICU). Research ethics committees approved the protocol in all jurisdictions. Research personnel prospectively collected standardized data for each consent encounter, including the consent model (a priori, deferred, or opt-out), the role of the individual who provided or declined consent (patient, SDM, other), and the reasons for declined consent, the role of the individual who requested consent (research coordinator, site investigator, ICU physician) and the consent encounter method (in person or via telephone). When consent was provided and then later revoked, who revoked consent (patient, SDM, other) and timing (in ICU, in hospital, post hospital), as well as details about permission for data retention were collected. In this study, consent rates will be calculated across REVISE sites, and in relation to the COVID-19 pandemic. We will also calculate the consent rates for a priori and deferred consent models, the timing from deferred recruitment to consent provided or declined, which personnel requested consent (research coordinator, site investigator, ICU physicians, other), and who engaged in the consent encounter for each consent model (patient, SDM, other). Multilevel logistic regression analysis will be conducted to evaluate variables independently associated with consent including additional site and staff variables. Results By analyzing the frequency and impact of consent models, and consent encounters with various stakeholders, results will highlight the acceptability of different approaches, and the impact of different approaches in this critical care trial. Conclusions This pre-planned retrospective sub-study using an international randomized controlled trial database will provide useful informed consent metrics and knowledge that is relevant to contemporary global trial conduct.

In 2013, a group of clinicians on behalf of the National Institute for Health Research, collaborated with ICU Steps to produce guidance about people being enrolled in more than one critical care trial. This is referred to as "co-enrolment" and can be where a person takes part in one study at the same time as another study (or one after the other in a short time-frame). For instance, being part of a study looking at sepsis drugs and a mechanical ventilation weaning study. The drivers for developing this guidance were a lack of any existing guidance, nationally and internationally, at that time, and a desire to ensure high quality research is conducted. The emphasis was on making trials as safe as possible for patients and ensuring robust trial outcomes. Critical care was seen to lead in this, with our exemplar guidance used across all health research. We wish to revisit this guidance now that there is more experience of coenrolment in critical care trials. There is also more awareness of different consent models, such as deferred consent (taking consent when a person is awake and able to give consent) and consultee consent (asking families or independent professionals to consent). Consenting to coenrolment is an important ethical consideration for the revision of this guidance.

Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance.

To summarise the temporal trends of recruitment and methodological characteristics of critical care randomised controlled trials with the primary outcome of mortality. PubMed was searched for articles meeting inclusion and exclusion criteria. Randomised controlled trials, with primary outcome of mortality, of adult and paediatric critical care patients treated in an intensive care unit, were included. Neonatal intensive care unit trials, non-English publications and conference proceedings or abstracts without full-length publications were excluded. Duplicate literature search, article selection and quality assessment were performed by two reviewers with disputes resolved through discussion. Data were extracted into a custom-designed Research Electronic Data Capture database. The search identified 67,199 records of which 230 were included. The annual number of critical care randomised controlled trials published increased gradually over a 30-year period from 0 in 1990 to 19 in 2014 with stabilisation at 8-11 between 2015 and 2020. Twenty-seven percent of randomised controlled trials were low risk in all categories using the Cochrane Risk of Bias tool. Methodological characteristics such as registration on clinical trials registries and data safety monitoring committee presence significantly (p < 0.001) increased over time. The median recruitment was 376 patients (interquartile range 125-895) with significant increase (p = 0.002) from 62 (interquartile range: 33-486) in 1991 to 725 (interquartile range: 537-2600) in 2020. This was accompanied by an increase in recruitment times. Thus overall, recruitment rates did not increase. Early cessation occurred in 23% (54/230) of randomised controlled trials with no temporal trend. The number, size and some methodological qualities of critical randomised controlled trials with primary outcome of mortality have increased over time, but rates of recruitment and early cessation have been unchanged.

Respiratory syncitial virus (RSV) is the leading cause of respiratory infections in infants and toddlers 1 and often presents as bronchiolitis. RSV infections represent a relevant burden of care for paediatricians and critical care physicians. But despite their common occurrence, only a few novel therapeutic interventions have been studied in this area, and research efforts have clearly been complicated by many factors. This is the case with continuous positive airway pressure (CPAP). Having established a wide and successful role in neonatal and adult critical care, CPAP had been inconsistently used for older infants and lack of evidence has prevented its wider application. Reasons for this discrepancy might be as follows: (i) the relatively paucity of paediatric intensive care units (PICUs) compared with neonatal units, causing regionalisation of care and a possible loss of research data, (ii) the lack of definite PICU research networks, (iii) the lack of strong and/or feasible endpoints, because of the low mortality rates for RSV infections. All of this makes it difficult to design high-quality clinical studies. In this issue of Acta Paediatrica, Borckink et al. 2 have made commendable efforts to overcome the barriers mentioned above. They used two PICU databases to create an adequate study population and tried to focus on more feasible endpoints, mainly reporting shorter ventilation times and PICU stays in infants treated with CPAP. Obviously, the study design is still not of a high quality although appropriate statistical methods have been applied to correct some flaws. In fact, the main biases are the retrospective cohort design, the presence of two groups coming from two entirely distinct PICUs, the lack of randomisation, some differences in clinical policies between the units and the different baseline severity of the patients. A multivariate analysis and a power calculation partially compensate these biases. However, to its credit, this study has taken a step towards designing randomised clinical trials (RCT) in paediatric critical care, particularly in an area where it is really needed. In fact, some studies have been published mixing together CPAP and non-invasive ventilation or focusing on patients affected by other conditions more severe than bronchiolitis 3. A search performed on September 27, 2013, using the following words and/or medical subject heading (MeSH) terms – (i) ‘infant’(MeSH terms) or (ii) ‘infant’ (all fields) and CPAP (all fields) and ‘bronchiolitis’ (MeSH terms) or (iii) ‘bronchiolitis’ (all fields) – yielded seven studies. These studies relied on small populations and uncontrolled designs 4-8. In other words, these research papers carry a much lower level of evidence. However, some data are also available from one RCT that was originally designed to study the combined use of heliox and CPAP 9 and from a small crossover RCT that interestingly reported reduced PaCO2 levels with CPAP use 10. Overall, these studies reported CPAP feasibility and safety. Useful data were reported on minor outcomes or for PICU stays or duration of respiratory support. The work carried out by Borckink et al. 2 is a controlled study and, as such, provides a higher level of evidence compared with previous ones and focuses on quite a homogeneous population. Based on the data the authors report in table 2, a sample size calculation (with α-error = 0.05, a power of 95% and a 1:1 randomization ratio) will require 60 infants per arm (assuming a reduction of about 40%) for the outcome ‘duration of ventilatory support’ and 81 infants per arm (assuming a reduction of about 40%) for the outcome ‘duration of PICU stay’. In these conditions, an RCT is clearly feasible, and investigators should take advantage of the efforts of Borckink et al., to create networks and conditions facilitating research. Even though the infant mortality for RSV infections is fortunately quite low, research should not be stopped in this domain, as RSV carries relevant burden of care and socio-economical consequences. Thus, new outcomes should probably also be considered, and possible endpoint candidates include social outcomes, such as numbers of lost working days/patients or measures of PICU burden of care, and economical outcomes, such as cost of drugs and devices used during the hospitalisation. Scientific societies play an important role in identifying new outcomes and in facilitating the research to make it more useful from a public health perspective. The role of clinical investigators is finally changing from small, local, low-quality studies to wider collaborative and high-quality projects. This requires more time and greater efforts, but it is the only way to address those questions that remain unanswered.

Background: Pharmaceutical companies play an important role in new drug development and approval in an environment where performing RCTs has become increasingly costly and complex. However, myriad questions about the impact of clinical, surgical and radiotherapy interventions equally require adequate hypothesis testing in RCTs. A potential lack of funding for RCTs not directly related to new drug development might lead to important gaps in clinical knowledge. Methods: We searched PubMed for all RCTs published between 01/2009 and 12/2013 in breast cancer. All articles published in this period were manually screened for eligibility. We included only RCTs with clinical endpoints such as TTP, PFS, OS and response rate. Two investigators independently selected phase 2 and phase 3 RCTs with at least 50 patients published in English. We also searched National Cancer Institute (NCI) data for all active, therapeutic phase 3 trials that are currently enrolling patients (as of 05/05/2014). We classified eligible trials according to the type of intervention (drugs, radiotherapy or surgery) and the stated funding source (industry versus nonprofit). Results: We retrieved 1,676 PubMed studies of which 247 (15%) were eligible. 218 (88%) of the RCTs evaluated drugs, 14 (6%) radiotherapy and 15 (6%) surgery. 183/247 (74%) RCTs were funded entirely or partially by industry (pharmaceutical and device companies) and 64/247 (26%) by nonprofit organizations (government, academic centers or foundations). There was a significant association between source of funding and type of intervention: 183/218 RCTs (83%) evaluating drugs were funded by industry, in comparison to none of surgical and radiotherapy RCTs (P&amp;lt;0.0001). From the NCI data we retrieved 144 RCTs. 116 (81%) of the RCTs studies drugs, 20 (14%) radiotherapy and 7 (5%) surgery. 55/116 (47%) trials evaluating drugs were funded by industry in comparison to none of surgical and radiotherapy trials. Eighty eight trials were not funded by industry. Of those, 23(26%) were performed in China, 16(18%) in the USA, 10 (11%) in France, 7 (8%) in India, 6 (7%) in the UK and the remaining 26 studies were performed in 16 other countries Conclusions: The vast majority of RCTs in oncology relates to drug development and is being funded by industry, while 100% of RCTs evaluating surgical or radiotherapy related questions are not industry funded. This scenario seems not be changing over the last years given that the comparison between published trials and active trials shows the same scenario. Even though new drug development is of paramount importance, the extent to which clinically relevant issues are not being properly addressed by RCTs, at least in part due to lack of funding, should be considered and further evaluated. The oncologic community, as well as academic and nonprofit organizations, including governments, need to work together to forge new and alternative forms of research funding in order to allow us to answer critical clinical questions that we, as oncologists, face in our daily practice. Citation Format: Artur Katz, Fernando Santini, Fabio Y Moraes, Andrea K Shimada, Caroline Chaul, Manuel C Abraao, Everardo D Saad. Relationship between type of therapeutic intervention and funding source in randomized clinical trials (RCTs) in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-18-02.

Aripiprazole versus other atypical antipsychotics for schizophrenia.

Researchers designing pragmatic, multi-centre randomised controlled trials (RCTs) in critical care are faced with numerous potential methodological challenges. These challenges can be outlined using PICO terminology:

To assess the general public's attitudes toward various consent models and data management strategies for critically ill adults eligible to participate in a low-risk randomized trial. A self-administered survey was conducted at public locations in Toronto to elucidate the general public's attitudes toward various consent models for participation in a low-risk randomized trial when a substitute decision maker was available, unavailable, or did not exist, as well as to assess attitudes toward strategies for data management in patients enrolled under a substitute decision maker's consent who later decline further participation. We surveyed 221 citizens. Most respondents (64%-74%) wanted to be considered for participation. When a substitute decision maker was available, similar proportions of respondents were comfortable with the substitute decision maker providing consent, deferred consent, and their substitute decision maker being asked if the respondent would "object to participating." If a substitute existed but was unavailable, most participants were comfortable with waived consent. If a substitute did not exist, respondents expressed comfort with 4 consent models: an attending physician model, a 2-physician model (1 involved in care), deferred consent, and waived consent. Compared with any physician, respondents preferred their attending physician to be involved in decisions about their research participation, especially in the absence of a substitute decision maker. Nearly three-fourths of respondents supported data management strategies that enabled use of their primary outcome; moreover, 58% believed that data collected before their decision to decline further participation should be included. Most respondents were interested in participating in a low-risk trial. Respondents endorsed a variety of approaches to obtaining consent in the presence or absence of substitute decision makers and many would be comfortable if their data were used despite a decision to decline further participation.

BACKGROUND: Randomized clinical trials (RCT) in critical care mostly return negative results. The research community discusses strategies to improve RCTs design. METHODS: This paper presents a theoretical framework based on marginal utility to treat the problems of hypothesis generation and treatment effects valuation and presents recently published high-quality studies as instances where such a framework predicts irrelevant findings. RESULTS: Blindness to marginal utility, i.e., inobservance of the marginal utility of the proposed intervention, is common in critical care RCTs. CONCLUSION: Critical care RCTs are usually blind to marginal utility and are, therefore, prone to produce irrelevant findings.