Summary points | Open Questions |
---|---|
Minimum validity and reliability criteria need to be fulfilled before engaging in a confirmatory multicenter study (Table 1) | Are dose–response effects a prerequisite for the confirmation? |
If uncertainty is still high, optimization of evidence via (within-lab, in-house) replication studies to (i) increase sample size, (ii) improve internal validity, (iii) introduce systematic homogenization and/or (iv) flanking experiments | What if evidence from pilot, exploration and within-lab replication are contradictory (positive and negative results)? |
(Standardized) protocols should be in place before starting a confirmatory study | - |
(Animal) Model(s) should be disease relevant and limitations be acknowledged | - |
Depending on the experimental objective control groups should include positive, negative controls and/or in case available a comparator from standard clinical care | What requirements need to be fulfilled to use historical control groups? |
For planning a confirmatory study, sample size calculation should be based on smallest effect (size) of interest (clinical/biological relevant) or a shrinkage of the effect size(s) from exploratory studies should be considered | Field specific effect sizes distributions are scarce, how can the situation be improved? What is the optimal approach to calculate the sample size? |
Flanking experiments (triangulation) might be performed early on and are highly recommended for confirmatory studies | How can in vitro studies be integrated in the confirmatory study design and sample size calculation? |
Introduction of sources of variation like sex or strain (systematic heterogenization) | How to best balance standardization and systematic heterogenization? |
Multicenter considerations include (i) harmonization of protocols, (ii) skills and expertise of partner lab(s), (iii) balanced design and (iv) block randomization across centers | Which experiments should be confirmed in several laboratories? |