Quality Improvement

Ulrich Dirnagl, Director Department of Experimental Neurologie and Scientific Director of the CSB
Ulrich Dirnagl

Improving the quality of translational research

My growing frustration regarding the difficulties to translate basic research to novel and effective therapies in stroke in particular, and in biomedicine in general, has kindled my interest to study the underlying causes of this ‘translational bottleneck’. Disturbingly, I discovered that the predictiveness of biomedical research is impaired by quality issues. On the positive side, since we scientists are responsible for the quality of our research, we can improve it right away. Consequently, together with fellow scientists I started to work on increasing the power of our experimental designs, to reduce bias, and to improve the internal as well as external validity, and the reporting of our research. Projects include (among others) the implementation of systematic quality management, systematic reviews, general research on the quality of preclinical translational medicine, international phase III type preclinical trials, all of which are summarized below.

Systematic Quality Management

There is consensus that the quality of biomedical research needs to be improved. ‘Quality’ is a broad and generic term, and it is clear that a plethora of factors together determine the robustness and predictiveness of basic and preclinical research results. Against this background the experimental laboratories of the Center for Stroke Research Berlin (CSB, Dept. of Experimental Neurology) have decided to take a systematic approach and to implement a structured quality management system. In a process involving all members of the department from student to technician, post doc, and group leader in over more than one year we have established standard operating produres, defined common goals and indicators, improved communication structures and document management, implemented an error management, are developing an electronic laboratory notebook, among other measures. On July 3rd 2014 this quality management system successfully passed an ISO 9001 certification process (Certificate 12 100 48301 TMS). The auditors were impressed by the quality oriented ‘spirit’ of all members of the Department, and the fact that to their knowledge the CSB is the first academic institution worldwide which has established a structured quality management in experimental research of this standard and reach. The CSB is fully aware of the fact that the mere fact that a certified quality management has been implemented does not guarantee translational success. However, we believe that innovation will only have impact on the improvement of the outcome of patients if it thrives on the highest possible standards of quality. Certification of our standards renders them transparent and verifiable to the research community, and serves as a first step towards a preclinical medicine in which research conduct and results can be monitored and audited by peers.


  • Dirnagl U. Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab. 2006;26:1465-78.
  • Macleod MR, Fisher M, O'Collins V, Sena ES, Dirnagl U, Bath PM, Buchan A, van der Worp HB, Traystman R, Minematsu K, Donnan GA, Howells DW. Good laboratory practice: preventing introduction of bias at the bench. Stroke. 2009;40:e50-2.

Research on quality and predictiveness of translational neuroscience

Systematic review and meta-analysis of preclinical studies are important tools to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research, and to improve the conduct and reporting of randomized controlled trials in clinical research. They can also inform the decision whether to take a preclinically promising treatment into a clinical testing in patients.  We are a member of the CAMARADES collaboration (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) which provides a supporting framework for groups involved in the systematic review and meta-analysis of data from experimental animal studies. Some of the systematic reviews we have conducted are listed below . Currently we are investigating the reporting of group sizes (or lack thereof...) in experimental stroke research.  

We also engage in the analysis of current research approaches in preclinical research, and propose improvement in strategy. For example, together with Kimmelman and Mogil we argue that distinguishing between exploratory and confirmatory preclinical research can improve  translation. Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge  is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. We recommend that research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.


  • CAMARADES Crossley NA, Sena E, Goehler J, Horn J, van der Worp B, Bath PM, Macleod M, Dirnagl U. Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke. 2008;39:929-34.
  • Dirnagl U, Macleod MR. Stroke research at a road block: the streets from adversity should be paved with meta-analysis and good laboratory practice. Br J Pharmacol. 2009;157:1154-6.
  • Kimmelman J, Mogil JS, Dirnagl U. Distinguishing between exploratory and confirmatory preclinical research will improve translation. PLoS Biol. 2014 May 20;12(5):e1001863. Macleod MR, Michie S, Roberts I, Dirnagl U, Chalmers I, Ioannidis JP, Al-Shahi Salman R, Chan AW, Glasziou P. Biomedical research: increasing value, reducing waste. Lancet. 2014;383:101-4.
  • Macleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke. 2008;39:2824-9. 
  • Vesterinen HM, Egan K, Deister A, Schlattmann P, Macleod MR, Dirnagl U. Systematic survey of the design, statistical analysis, and reporting of studies published in the 2008 volume of the Journal of Cerebral Blood Flow and Metabolism. J Cereb Blood Flow Metab. 2011;31:1064-72
  • Watzlawick R, Sena ES, Dirnagl U, Brommer B, Kopp MA, Macleod MR, Howells DW, Schwab JM. Effect and reporting bias of RhoA/ROCK-blockade intervention on locomotor recovery after spinal cord injury: a systematic review and meta-analysis. JAMA Neurol. 2014;71:91-9.

International phase III trials in preclinical stroke research

Translational stroke medicine requires renewal, and international collaboration in preclinical research may be an important step to overcome hurdles impeding progress. The tremendous power of international research collaboration has been convincingly demonstrated in physics, and several transnational collaborations have already delivered proof of concept in the stroke field. The experience gleaned from such collaborations is paving the way for an exciting new era in stroke research, which strives to harness the multitude of benefits achievable through international collaboration. At the CSB we have taken concrete action to advance the agenda and together with colleagues from Europe, North America, and Australia are establishing an international preclinical stroke network. In several bottom-up initiatives we have started to conduct phase III type randomized controlled preclinical trials to obtain robust evidence for or against the efficacy in rodent models of stroke of promising new treatments. In the European Union funded initiative Multi-PART (Multicentre Preclinical Animal Research Team) we are developing the capacity to undertake international multicentre animal studies to improve the validity, and generalisability of current preclinical research to improve the prospects of success for translation of efficacy to human clinical trials. We propose a paradigm shift to perform experimental studies with the same rigour, and driven by the same central coordination, as has proven successful in multicentre phase-III randomised controlled clinical trials in humans. Multi-PART will establish a platform with the potential to transform preclinical animal research, similar to the tremendous improvements in clinical research that occurred through the introduction of multicentre clinical trials. Through a “worked example” of animal modelling of ischaemic stroke, our consortium will define the elements of a successful multicentre animal trial and will describe the tools (technical, regulatory, organisational) that will allow such studies to be conducted, either by Multi-PART or by other consortia.  This will inform the design and conduct of adequately powered multicentre animal studies with improved internal and external validity, not just in stroke but also for other disease models.


  • Dirnagl U, Hakim A, Macleod M, Fisher M, Howells D, Alan SM, Steinberg G, Planas A, Boltze J, Savitz S, Iadecola C, Meairs S. A (2013) Concerted Appeal for International Cooperation in Preclinical Stroke Research. Stroke. 44:1754-60.
  • Dirnagl U, Fisher M. (2012) International, multicenter randomized preclinical trials in translational stroke research: it's time to act. J Cereb Blood Flow Metab.;32:933-5.   
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