Gilad Rosenberg, MD, MSc, Executive Medical Director, Therapeutic Area Medical Lead in Neuroscience
Acute ischemic stroke (AIS) is a common and often devastating illness. Each year close to 700,000 persons experience new or recurrent ischemic stroke in the US alone. While the development of effective treatments for AIS is a priority of neurological research, clinical trials in AIS are hindered by a variety of issues. This blog reviews some of the current difficulties enrolling patients into AIS trials, with a particular focus on obtaining informed consent.
Patient recruitment difficulties in AIS trials
Late-stage AIS trials require a large number of patients to achieve an adequate statistical power. However, recruiting patients into an AIS trial can be challenging due to a variety of factors, such as difficulty obtaining informed consent (discussed below), restrictive inclusion criteria, complicated trial design, and sites’ reluctance to participate. Recent publications have suggested remedying these issues by limiting the exclusion criteria only to those absolutely mandated by the biological effects of the experimental treatment, reducing the burden of follow-up visits by means of virtual meetings, assessing sites’ therapeutic equipoise and research enthusiasm as part of the site selection process, and simplifying trial design. The latter aim can be achieved through the implementation of research schemes such as the PROBE (Prospective, Randomized, Open, Blinded Endpoint) design – which has already been used in several acute stroke trials in recent years – or of adaptive designs, e.g., in early phase trials where dose selection is the primary aim. Additionally, trials in AIS – a condition requiring urgent treatment – often have limited temporal window for inclusion, typically just a few hours following symptoms’ onset or after ‘last seen well’. However, evidence from interventional AIS thrombectomy trials over the last decade indicates that at-risk but salvageable brain tissue (known as ‘penumbra’) may be present in multiple patients many hours after stroke onset, which can be confirmed on an urgent basis using imaging techniques available in many medical centers, e.g., perfusion CT. Future AIS trials with either therapeutics or devices may therefore enjoy a longer time window for inclusion compared to previous trials, making enrollment easier.
Informed consent and its deferral
Difficulties in obtaining informed consent in AIS trials are widely recognized. Although uncommon and legally challenging in the USA, the deferral of consent has become increasingly prevalent in Canada and Europe in recent years. Deferral of consent offers several theoretical benefits over prospective consent: it may increase trial enrollment rate and thus shorten trial timelines, reduce onset-to-treatment time (a crucial consideration in AIS), and diminish the generalizability problem inherent in including only patients able to consent. To date, however, these alleged advantages haven’t been unequivocally substantiated; furthermore, there is a clear ethical risk in enrolling patients – potentially against their wish – into a trial that may inadvertently result in harm. Given that few patients leave advance directives about the treatments and that surrogate decision-makers (e.g., next of kin) often have difficulties speculating on the patient’s wishes, this problem clearly merits innovative thinking.
There seems to be a general agreement that deferring consent is justified only if there is a realistic possibility of direct benefit to the participant, implying that consent deferral should be avoided in early phase research and applied only in Phase III trials, where some evidence supporting an effect already exists from earlier trials. Additionally, consent deferral must be exercised only if the participant’s premorbid preferences are unknown and if it is unfeasible to obtain surrogate consent given the emergency. This is true as long as informed consent for continued participation is obtained at the earliest opportunity after trial enrollment (and, of course, provided that the consent deferral procedure has been approved by an IRB).
With this in mind, Faris and colleagues1 recently proposed a protocolized approach for consent deferral in AIS trials, which might minimize the aforementioned ethical risks. This approach has been used in the recent Alteplase Compared to Tenecteplase (AcT) trial. Based on 6 principles, the approach requires: (i) designation of a trial “ethics lead”, as an assurance that all applicable laws and regulations are followed; (ii) involvement of persons with relevant experience (e.g., patient partners) in trial planning and in the trial’s steering committee; (iii) early publication of the justification and protocol for consent deferral, to ensure transparency and peer review; (iv) facilitation of physician-surrogate decision maker communication through scripts and other aids (with relevant training); (v) monitoring of the withdrawal rate of subjects enrolled under deferred consent, reporting deviations from a prespecified ‘acceptable withdrawal rate’ to the trial’s governing bodies (e.g., steering committee); and (vi) ongoing monitoring of participants’ attitude toward consent deferral once their consent capacity is regained. It remains to be seen whether this approach will gain the support of patient advocacy groups, regulators and medical professional societies.
Conclusion
Clinical trials in AIS pose several patient enrollment challenges that can hinder the development of new drugs or devices for this indication. However, the use of deferred consent, permissive inclusion criteria, novel trial designs and extended temporal treatment windows may offer solutions to some of these challenges.
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