A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation

Pamela W. M. Kleikers, Carlijn Hooijmans, Eva Goeb, Friederike Langhauser, Sarah S. J. Rewell, Kim Radermacher, Merel Ritskes-Hoitinga, David W. Howells, Christoph Kleinschnitz, Harald H. H. W. Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Web of Science)


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.
Original languageEnglish
Article number13428
JournalScientific Reports
Publication statusPublished - 27 Aug 2015

Cite this