Selection bias in clinical stroke trials depending on ability to consent

Hotter et al. BMC Neurology (2017) 17:206 DOI 10.1186/s12883-017-0989-9 RESEARCH ARTICLE Open Access Selection bias in clinical stroke trials depending on ability to consent Benjamin Hotter1,2,3* , Lena Ulm1,2,3,4, Sarah Hoffmann1,2,3, Mira Katan5, Joan Montaner6, Alejandro Bustamante6 and Andreas Meisel1,2,3 Abstract Background: Clinical trials are the hallmark of evidence-based medicine, but recruitment is often challenging, especially in stroke trials investigating patients not being able to give informed consent. In some nations, ethics committees will not approve of inclusion in a clinical study via consent of a legal representative. The ethical dilemma of including or excluding those patients has not been properly addressed, as there is little data on the effect of stroke characteristics on the ability to give informed consent. Methods: To examine differences between patients able and unable to consent at inclusion to an acute stroke trial, we conducted a post-hoc analysis of monitoring records from a multicentric interventional trial. These records listed patients who gave informed consent by themselves and those who needed a legal representative to do so. This exemplary STRAWINSKI trial aimed at improving stroke outcome by biomarker-guided antibiotic treatment of stroke associated pneumonia and included patients within 40 h after stroke onset, suffering from MCA infarctions with an NIHSS score > 9 at admission. Standard descriptive and associative statistics were calculated to compare baseline characteristics and outcome measures between patients who were able to consent and those who were not. Results: We identified the person giving consent in 228 out of 229 subjects. Patients with inability to consent were older (p < 0.01), suffered from more left-hemispheric (p < 0.01) and more severe strokes (NIHSS, p < 0.01), were more likely to die during hospitalisation (p < 0.01) or have unfavourable outcome at discharge (mRS, p < 0.01), to develop fever (p < 0.01) and tended to be more susceptible to infections (p = 0.06) during the acute course of the disorder. Conclusions: Demographics, stroke characteristics and outcomes significantly affect stroke patients in their ability to consent. Where selection criteria and primary outcome measures of a trial are significantly affected by ability to consent, excluding patients unable to consent might be unethical. Trial registration: URL http://www.clinicaltrials.gov. Unique identifier: NCT01264549. Keywords: Stroke, Clinical trial, Informed consent, Ethics, Methods, Selection bias Background Clinical trials often suffer from low recruitment with subsequently prolonged duration of the trials [1]. Previous work has identified special obstacles stroke research has to face. Not only is the time window of intervention limited by pathophysiological circumstances, but also, ability of patients to provide informed consent is frequently impeded due to disabilities caused by the stroke * Correspondence: 1 Center for Stroke Research Berlin, Charité University Hospital Berlin, Charitéplatz 1, 10115 Berlin, Germany 2 Department of Neurology Berlin, Charité University Hospital Berlin, Charitéplatz 1, 10115 Berlin, Germany Full list of author information is available at the end of the article itself [2–4]. Regulatory approaches to clinical research with patients unable to give informed consent themselves differ substantially between countries [5, 6]. In the USA, regulations differ strongly between federal states, with some of them not having formal criteria of what constitutes a sufficiently authorized legal representative, leaving interpretation to investigators and ethics committees. In some countries – like Germany – the authorization to obtain informed consent by a legal representative might even be declined totally in one federal state, but granted in another. Some legislators - for instance in the USA and United Kingdom – now provide a framework for exceptions or “waivers” of consent to address this issue, © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hotter et al. BMC Neurology (2017) 17:206 Page 2 of 7 frequently with a list of criteria the target population and the trial need to meet [7, 8]. Usually these include the condition studied to be acutely life-threatening, with unsatisfactory treatment options, frequently or regularly rendering the patients unable to consent. While the incapacity to consent is widely recognized as a major obstacle as well as an ethical dilemma of clinical trials in critical care, neurology and cognitive decline [9, 10], quantitative data characterising consenting and influencing parameters in these settings are very limited [11, 12]. The third international stroke trial (IST-3) reported different stroke severity and outcome based on the method of consent, but stands alone in the field of stroke research to do so [13]. This issue is of major significance, since some treatments can only be studied in patients severely affected by stroke. Patients who are only mildly affected have a higher probability to recover without any intervention [14]. The ability to consent is strongly linked to age, the severity and localisation of stroke [3, 15]. Furthermore, stroke-related complications such as post-stroke infections mainly occur in severely affected patients. Dysphagia and Central Nervous System-injury induced immune depression syndrome are the main risk factors for stroke-associated pneumonia (SAP) [16–18]. The frequency of SAP strongly correlates with the National Institute of Health Stroke Scale (NIHSS) score at admission [19]. To investigate possible selection bias introduced into clinical trials based on ability to give informed consent we analysed data from the “STRoke Adverse outcome is associated WIth NoSocomial Infections” (STRAWINSKI) trial. The trial was designed to analyse treatment-guidance for antibiotics by the use of ultrasensitive Procalcitonin (PCTus) as a marker for bacterial infections. For STRAWINSKI regulatory authorities granted permission to include patients by a legal representative (usually a nextof-kin) as well as by personal informed consent. Based on an explorative analysis we aimed at identifying differences between both groups in order to estimate the bias introduced when only including patients able to give informed consent personally. approved by the appropriate ethics committees (Charité - Universitätsmedizin Be (...truncated)