OBJECTIVES: Atrial fibrillation (AF) has been identified by the Institute of Medicine as one of the top research priorities for comparative effectiveness research, yet there is limited methodological guidance on how to meet the evidentiary needs of patients, clinicians, and payers. The Center for Medical Technology Policy (CMTP) managed a stakeholder-driven process to develop an effectiveness guidance document that issued guidance for trial designers on study design considerations to best answer decision-makers’ needs in AF research.   METHODS:  The AF team reviewed the literature and conducted interviews with researchers, patients and methodologists to scope the project needs.  Open-question interviews were conducted with 25 individuals from the clinical research, clinical practice, regulatory, payer, professional organizations, and patient communities. An eight-person multi-stakeholder technical working group worked in collaboration with CMTP staff to establish and refine the recommendations.  The methods recommendations were guided by the objective of achieving an acceptable balance across a number of desirable dimensions, including internal validity, relevance, feasibility and timeliness. The document was posted on CMTP’s website for a 30-day public comment period as part of the broader dissemination and translation strategy.    RESULTS: The final recommendations provide guidance on the design of prospective studies in Atrial Fibrillation, rationale for their inclusion, specifics on implementation and data analysis/reporting considerations.  The final list included five research design recommendations, and three priority research areas that would synergistically benefit stakeholders’ evidentiary needs and improve health outcomes.   CONCLUSIONS: The meaningful engagement of patients, providers, and decision makers to prioritize the questions and develop the methods to answer them is an essential component of CER.  The Atrial Fibrillation methods guidance was developed in a unique process to improve the future quality of evidence with a balance between internal validity and external generalizability.