OBJECTIVES: In recent years, comparative effectiveness research (CER) has gained increasing interest and investment across major life science and health policy stakeholder groups: regulators, biopharmaceuticals, physicians, patients, and payers. One method, large simple trial (LST), a hybrid of observational cohort study and randomized control trial (RCT), is designed for large numbers of patients in post-approval research and is a choice study design for comparing the relative strengths and weaknesses of medical interventions. The objective of this study was to evaluate the current landscape of LSTs to capture key themes in the future outlook of CER. METHODS: A structured abstract review and funnel analysis was conducted using data available through ClinicalTrials.gov. Using the search terms, “phase IV”, “post-marketing”, “randomized”, and “multi-centered”, 2230 clinical trials were filtered with restricted parameters for number of patients (n>1000), evidence of blinding, stated objective of comparative effectiveness, and date of trial initiation. RESULTS: To gain a perspective on current and future outlook, only trials initiated between 2009 and 2010 (n=10) were assessed in this phase of study. Using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS) framework originally developed for pragmatic trials, the analysis revealed an important theme. When applying key domain criteria – practitioner expertise, treatment flexibility, eligibility criteria, health outcomes, study duration, intent-to-treat (ITT), and primary outcome analysis, as defined by the PRECIS framework – less than 50% of the LST CER trials were designed to measure effectiveness, as opposed to efficacy. CONCLUSIONS: According to findings, there has been an uptake on the use of LSTs in investigating the relative effectiveness of interventions. However, considering the increase in governmental pressure to reduce healthcare spending by improving quality of treatment; it is important that these LSTs are conducted to truly capture effectiveness. For that reason, there is need for further research to extract and develop new frameworks for evaluation.