Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report
Creators: name: Drude, Natascha Ingrid
name: Martinez-Gamboa, Lorena
name: Danziger, Meggie
name: Collazo, Anja
name: Kniffert, Silke
name: Wiebach, Janine
name: Nilsonne, Gustav
name: Konietschke, Frank
name: Piper, Sophie K.
name: Pawel, Samuel
name: Micheloud, Charlotte
name: Held, Leonhard
name: Frommlet, Florian
name: Segelcke, Daniel
name: Pogatzki-Zahn, Esther M.
name: Voelkl, Bernhard
name: Friede, Tim
name: Brunner, Edgar
name: Dempfle, Astrid
name: Haller, Bernhard
name: Jung, Marie Juliane
name: Riecken, Lars Björn
name: Kuhn, Hans-Georg
name: Tenbusch, Matthias
name: Higuita, Lina Maria Serna
name: Remarque, Edmond J.
name: Grüninger-Egli, Servan Luciano
name: Manske, Katrin
name: Kobold, Sebastian
name: Rivalan, Marion
name: Wedekind, Lisa
name: Wilcke, Juliane C.
name: Boulesteix, Anne-Laure
name: Meinhardt, Marcus W.
name: Spanagel, Rainer
name: Hettmer, Simone
name: Lüttichau, Irene Von
name: Regina, Carla
name: Dirnagl, Ulrich
name: Toelch, Ulf
Publisher: name: Charité - Universitätsmedizin Berlin
Year: 2022
Subjects: subject: Confirmatory preclinical studies
subject: Confirmatory preclinical multicenter studies
subject: Preclinical multicenter studies
subject: Robust evidence
subject: Reproducibility
subject: Clinical translation
subject: Translational biomedical research
subject: Multi-stakeholder workshop
subject: 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

description: Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solutionoriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory.