title: A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation.
abstract: Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2(-/y) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.
authors: Department of Pharmacology, CARIM, Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands.
authors: Pamela W M
authors: PW
authors: Kleikers
authors: SYRCLE at Central Animal Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Carlijn
authors: C
authors: Hooijmans
authors: Neurologische Klinik und Poliklinik der Universitätsklinik Würzburg, Würzburg, Germany.
authors: Eva
authors: E
authors: Göb
authors: Neurologische Klinik und Poliklinik der Universitätsklinik Würzburg, Würzburg, Germany.
authors: Friederike
authors: F
authors: Langhauser
authors: Florey Institute of Neuroscience and Mental Health, Austin Health, Melbourne, Victoria, Australia.
authors: Sarah S J
authors: SS
authors: Rewell
authors: Department of Pharmacology, CARIM, Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands.
authors: Kim
authors: K
authors: Radermacher
authors: SYRCLE at Central Animal Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Merel
authors: M
authors: Ritskes-Hoitinga
authors: Florey Institute of Neuroscience and Mental Health, Austin Health, Melbourne, Victoria, Australia.
authors: David W
authors: DW
authors: Howells
authors: Neurologische Klinik und Poliklinik der Universitätsklinik Würzburg, Würzburg, Germany.
authors: Christoph
authors: C
authors: Kleinschnitz
authors: Department of Pharmacology, CARIM, Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands.
authors: Harald H H W
authors: HH
authors: Schmidt
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000150:complications / Q000473:pathology; D005260:Female; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D019255:NADPH Oxidases / Q000378:metabolism*; D017594:Publication Bias; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D058028:Research Report; D013223:Statistics as Topic; D020521:Stroke / Q000150:complications / Q000201:enzymology
chemical_list: D019255:NADPH Oxidases