In the context of emerging diseases, such as Ebola, Dengue or Zika, implementing the gold-standard individually randomized, double-blind, placebo-controlled trial to evaluate the effect of prophylactic interventions on preventing infections, may not always feasible. Infection rates may vary heavily from region to region as well as over time (outbreaks, hotspots). This in turn may provide both logistically difficult and/or ethically problematic when the risk is high (such as Ebola virus disease). Development of an appropriate study design in this context requires innovative thinking and thorough quantitative evaluation of study design, sample size and analysis methods. Epidemiological infectious disease modeling combined with statistical clinical trial modeling and simulation could be a powerful tool for planning and evaluating various effectiveness designs. Through case studies, this presentation will illustrate the modeling tools employed and how they were used to guide effectiveness study design, development and decision-making.