Comparative effectiveness research (CER) has a number of features that distinguish it from clinical research in general (1,2). CER is, in essence, framed by asking the core question: for a doctor and a patient, what is the best treatment for that patient in terms of both benefits and harms? To answer that question, the process essentially would require effective translation of the following issues: 1 ) head-to-head comparisons of the proposed interventions versus the best available alternatives; 2 ) emphasis on both benefits and harms, the harms often having the most immediate impact on the patients; 3 ) the examinations of effectiveness in key subgroups within a disease, so that a given patient and doctor can easily match the patient with that group; 4 ) the study of multiple relevant outcomes, each having adequate power to detect differences; and 5 ) the impact of the provider, and the differential quality rendered, especially in large multicenter trials. Highlighting these features has given rise to the notion that, in addition to classic randomized controlled trials (RCTs), “pragmatic” trials must be conducted. Further, observational studies carried out through registries or other databases need to be used to detect uncommon but important harms, to provide data on subgroups not included in trials or included in small numbers, and to evaluate the effectiveness of care in community settings. In short, the overarching goal of a comparative effectiveness exercise is to ask a very simple question, “Does an intervention work, and if so, for whom and …