Effect of waivers of consent on recruitment in acute stroke trials

Abstract

There is urgent need for clinical trials of novel interventions to reduce the burden of acute ischemic stroke. A key impediment to such trials is slow recruitment. Since obtaining written informed consent in the setting of acute stroke is especially challenging, some experts have endorsed relaxing the requirement for informed consent by permitting verbal consent or waivers to facilitate recruitment. This systematic review of 36 randomized controlled trials of acute interventions for ischemic stroke assesses whether alternatives to written informed consent are associated with increased recruitment rates. After the exclusion of 2 outlier trials that differed from other trials in conduct and interventions studied, no association was observed on univariable analysis (8.9 participants/month in trials requiring written consent vs 6.1 participants/month in trials with alternatives, p 5 0.43) or multivariable analysis (when adjusting for the number of centers, number of countries, and exclusions based on modified Rankin Scale scores). Alternatives to written informed consent in acute stroke trials may enable trial designs that would not be feasible otherwise. However, we did not find evidence that, within traditional trial designs, such alternatives are associated with faster recruitment. Despite sweeping advances in stroke prevention and treatment including cardiovascular risk modification, acute reperfusion therapies, extensive public education, the establishment of stroke centers and systems of care, and new technologies such as telemedicine and imagingbased patient selection for endovascular treatment, ischemic stroke remains a leading cause of major disability and death. In recognition of the continuing need to improve outcomes in acute ischemic stroke, the NIH recently established a network of more than 200 sites (NIH StrokeNet) to provide infrastructure for stroke clinical trials.1 However, one of the enduring challenges for most clinical trials (particularly for acute stroke trials) is slow recruitment, which poses a serious threat to feasibility and statistical power. The requirement for informed consent has been described as the rate-limiting step of acute stroke trials. 4 Obtaining informed consent for research poses numerous challenges for stroke clinical investigators. The stroke itself may render a patient aphasic or cognitively incapacitated. Multiple studies indicate that surrogate decision-makers, if available, are less willing to enroll incapacitated relatives in clinical research compared to when patients are given the option directly.5-7 The time window for intervention is narrow, which requires investigators to hastily obtain consent while preparing to deliver sometimes complex treatments. Recent trials testing hyperacute field-based interventions such as thrombolysis on mobile stroke units equipped with CT scanners have further narrowed the time window to obtain consent. 8,9 Finally, many established and investigational therapies involve a complex weighing of risks and benefits, such that m...

A systematic review of the efficiency of recruitment to stroke rehabilitation randomised controlled trials

“…A systematic review and metaanalysis of 114 large scale (> 300 participants) acute (within 1 month after stroke) pharmacological stroke trials published between 1990 and 2004 reported a mean recruitment rate of 0.79 participants per site per month [13]. An update of this study revealed a median recruitment rate of 0.41 participants per site per month for trials published between 2010 and 2014 [24]. Despite notable difficulties recruiting stroke survivors, and limited improvement over the past 27 years [13,14], little research has focused on recruitment of stroke survivors to rehabilitation RCTs.…”

“…Recruitment of stroke survivors to clinical trials is challenging [13,14,24]. In the UK more than 100,000 people experience a stroke each year [25,26] and there are currently 1.2 million people living with strokerelated impairments [27][28][29].…”

Trends in Recruitment Rates for Acute Stroke Trials, 1990–2014

“…12 The recruitment efficiency of that trial was 10.5 participants/site/month, and the recruitment rate was 294.4 participants/month—both far higher than the trials in this review and indeed far higher than other recent field-based trials with opt-in enrollment. 8 We specifically excluded field-based trials from this review to enable proper comparison of newer trials to those in the Elkins dataset, which included only hospital-based interventions. But field-based interventions designed to improve the speed with which stroke therapy is delivered may also enhance the recruitment of trials as more participants are reached before the time window for inclusion closes.…”

“…13 Opt-out strategies raise challenging ethical questions, which merit further examination, but they have gained increasing acceptance by institutional review boards (IRBs) and the Food and Drug Administration. 8 Whether such opt-out strategies become more prevalent in acute stroke trials remains to be seen.…”

“…The older trials (1990–2004) that serve as a comparator for analysis were included in a systematic review by Elkins et al 7 The 32 trials in that review were all hospital-based (as opposed to field-based) trials with more than 300 participants, 18 of which had interventions applied within 12 hours of symptom-onset. Our search strategy for identifying newer trials (2010–2014) has been reported elsewhere 8 and is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. 9 Our search yielded 36 trials, 10 of which were hospital-based trials with more than 300 study participants occurring within 12 hours of symptom-onset (Supplemental Figure I; Supplemental Table I).…”