Novel approaches to observational studies and clinical trials could improve the cost-effectiveness and speed of translation of research. Hybrid designs that combine elements of clinical trials with observational registries or cohort studies should be considered as part of a long-term strategy to transform clinical trials and epidemiology, adapting to the opportunities of big data and the challenges of constrained budgets. Important considerations include study aims, timing, breadth and depth of the existing infrastructure that can be leveraged, participant burden, likely participation rate and available sample size in the cohort, required sample size for the trial, and investigator expertise. Community engagement and stakeholder (including study participants) support are essential for these efforts to succeed.