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

2015-08-27

Kleikers, Pamela WM

Hooijmans, Carlijn

Göb, Eva

Langhauser, Friederike

Rewell, Sarah SJ

Radermacher, Kim

Ritskes-Hoitinga, Merel

Howells, David W

Kleinschnitz, Christoph

Schmidt, Harald HHW

Molecular Targeted Therapy

NADPH Oxidase

Randomized Controlled Trials as Topic

Journal Article

10.1038/srep13428

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.

link

Scientific Reports 2015; 5: 13428

Scientific Reports