Do stroke models model stroke?

Abstract

Stroke is one of the leading causes of death worldwide and the biggest reason for long-term disability. Basic research has formed the modern understanding of stroke pathophysiology, and has revealed important molecular, cellular and systemic mechanisms. However, despite decades of research, most translational stroke trials that aim to introduce basic research findings into clinical treatment strategies - most notably in the field of neuroprotection - have failed. Among other obstacles, poor methodological and statistical standards, negative publication bias, and incomplete preclinical testing have been proposed as 'translational roadblocks'. In this article, we introduce the models commonly used in preclinical stroke research, discuss some of the causes of failed translational success and review potential remedies. We further introduce the concept of modeling 'care' of stroke patients, because current preclinical research models the disorder but does not model care or state-of-the-art clinical testing. Stringent statistical methods and controlled preclinical trials have been suggested to counteract weaknesses in preclinical research. We conclude that preclinical stroke research requires (1) appropriate modeling of the disorder, (2) appropriate modeling of the care of stroke patients and (3) an approach to preclinical testing that is similar to clinical testing, including Phase 3 randomized controlled preclinical trials as necessary additional steps before new therapies enter clinical testing.

Fig. 1.

Based on randomized controlled clinical trials, the final stage of preclinical testing should be to conduct a randomized controlled preclinical trial. In this scenario, a steering committee agrees on the intervention to be tested and all related aspects (e.g. models, outcome parameters, etc.). All administrative matters are centrally organized by a preclinical research organization (pCRO) and include objective criteria for the recruitment of study sites, the modes of randomization, collection of the data from the study sites and central monitoring of all aspects of the trial. Ideally, all study sites are capable of performing the same experiments (i.e. they have access to the same models and equipment). All aspects of the randomized controlled preclinical trial are monitored by an independent organization.

Fig. 2.

The preclinical trial phases of translational stroke research. As therapeutic agents or concepts advance in development, the experimental setting increases in complexity. It ranges from small cohorts to investigate novel (pathophysiological) mechanisms to large mixed populations with (multiple) comorbidities and additional modeling of stroke care. The final stage of preclinical development is to conduct a randomized controlled preclinical trial (RCPT), ideally in a stroke unit setting. Randomized clinical trials commence after this process has been completed, and are based on evidence gained in preclinical testing.