Pragmatic Trials: Design, Methods, and Implementation

Course Aim
Pragmatic randomized clinical trials (pRCTs) require the expertise of pharmacoepidemiologists who understand considerations and methodologic challenges that arise with more "pragmatic" RCTs compared with traditional "explanatory" RCTs. This course will give an overview of current developments affecting pragmatic trial design planning and impact, review pRCT study designs including cluster randomization, step wedge design and platform trials, and summarize associated analytic considerations. Randomizing patients to "standard of care (SOC)", blinding, accounting for changes in therapies over time, and other methodological considerations will also be discussed. Operational challenges and lessons learned from conducting pRCTs will be shared along with case examples.

Requisites Statement
Entry level, though familiarity with basic principles of observational and/or experimental study design and statistical methods is recommended. Recommended pre-course reading material will also be provided.

Course Objectives
· To understand key design considerations for pRCTs and drivers of design choices (including cluster randomized vs. patient level randomization)
· To understand statistical issues for the analyses of pRCTs
· To identify and address operational considerations and challenges in implementing pRCTs including newer technologies that support imbedding trials at point of care and leveraging of secondary data such as EMR to reduce patient and site burden.
· To gain insight into current and recent pragmatic trial case examples with regard to their methods, implementation, operational challenges, and intended use as real-world-evidence in support of pre- or post-market treatments

Syllabus Outline
1. Overview and Introduction to Pragmatic Trials-J Christian
To introduce attendees to the rationale and context for conducting pRCTs, a high level overview, explanation of the PRECIS criteria, pivotal studies and articles, and examples of impact with different stakeholders will be discussed.

2. Study designs for pragmatic trials — P Velentgas
The following topics related to study designs and outcome selection for pragmatic trials will be addressed: patient-level and cluster randomized designs, cross-over trials, and platform designs. Issues relating to blinding, inclusion and exclusion criteria, and choice of comparators will also be discussed, with illustrative case examples.

3. Statistical analyses for pragmatic trials — C Girman
Analytic methods related to pragmatic trials will be reviewed, including different considerations related to randomization, sample size estimation for cluster randomized and stepped wedge designs, appropriate analysis methods, and non-inferiority vs. superiority hypothesis testing.

4. Recent case examples of pragmatic trials funded by PCORI — A Trontell
Dr. Trontell will provide an overview of some of the recently completed PCORI-funded pragmatic trials, focusing on unique features of PCORI's approach and challenges of implementation. Investigator feedback on challenges in pragmatic trials and a patient-centered approach to design of such trials will also be given.