Thomas Willis Lecture

Over the past few decades, preclinical research on stroke has led to tremendous progress in our basic understanding of the pathophysiological events that follow focal cerebral ischemia. Numerous cellular and molecular targets have been identified for brain protective and restorative therapies, and many of these are highly effective in rodents. The incidence and morbidity and mortality of stroke have decreased. Stroke units and recanalization via intravenous tissue-type plasminogen activator or thrombectomy are impressive clinical success stories benefitting many patients. Intriguingly, however, practically none of these clinical breakthroughs are the result of bench-to-bedside translation. On the contrary, almost all therapies that were preclinically successful have failed in patients with actual stroke. This exceedingly high rate of attrition in translational stroke research has already been the subject of many articles. There are no simple explanations, and stroke research is certainly not the only biomedical field struggling with a translational roadblock. In the following, I would like to emphasize factors for which quantitative meta-analytic evidence exists that suggests that they contribute to attrition. My selection is biased toward items in the preclinical realm that pose straightforward opportunities for improvement. Inspired by work from bioethics and from meta-research, I would like to propose, counterintuitively there are instances where we need to embrace attrition. Collectively, I argue for an update of our intellectual framework for translational research. To a large extent, bench-to-bedside translation is a black box. Innumerable factors affect whether and to what extent preclinical evidence is transferable to clinical evidence. Attrition lurks on all levels: preclinically, when moving to first in man, when trying to obtain safety or initial signs of efficacy, and in large clinical trials aiming at regulatory approval.