Authors of a review published in Genetics in Medicine suggest hybrid study designs that “integrates elements of practice-based observational research and pragmatic trials hold the most promise for addressing priorities that include minimizing bias, accounting for co-interventions, identifying long-term impacts, and considering clinical heterogeneity”. According to the authors, investment in healthcare systems research for rare diseases in paramount and emphasize a need to identify the appropriate outcomes, study designs, and stakeholder – engagement strategies to facilitate the successful implementation of new therapies toward improved care and health for patients and their families. They review how effectiveness of outcomes can be defined for incremental and transformative therapies. They illustrate how ideal study designs can ensure that new therapies are translated appropriately to provide improved outcomes for patients. The authors emphasize the importance of actively engaging stakeholders for appropriately evaluating the value of these evidence-generation activities. They believe that a knowledge exchange infrastructure is needed to understand the priorities of stakeholders.