BACKGROUND:Bringing new therapies to patients with rare diseases depends in part on optimizing clinical trial conduct through efficient study start-up processes and rapid enrollment. Suboptimal execution of clinical trials in academic medical centers not only results in high cost to institutions and sponsors, but also delays the availability of new therapies. Addressing the factors that contribute to poor outcomes requires novel, systematic approaches tailored to the institution and disease under study. OBJECTIVE: To use clinical trial performance metrics data analysis to select high-performing cystic fibrosis (CF) clinical research teams and then identify factors contributing to their success. DESIGN: Mixed-methods research, including semistructured qualitative interviews of high-performing research teams. PARTICIPANTS: CF research teams at nine clinical centers from the CF Foundation Therapeutics Development Network. APPROACH: Survey of site characteristics, direct observation of team meetings and facilities, and semistructured interviews with clinical research team members and institutional program managers and leaders in clinical research. KEY RESULTS: Critical success factors noted at all nine high-performing centers were: 1) strong leadership, 2) established and effective communication within the research team and with the clinical care team, and 3) adequate staff. Other frequent characteristics included a mature culture of research, customer service orientation in interactions with study participants, shared efficient processes, continuous process improvement activities, and a businesslike approach to clinical research. CONCLUSIONS: Clinical research metrics allowed identification of high-performing clinical research teams. Site visits identified several critical factors leading to highly successful teams that may help other clinical research teams improve clinical trial performance.