Abstract

The widespread adoption of the randomized controlled trial (RCT) was the most important advance in clinical research in the 20th century. It has rightly become the gold standard for evaluating the causal effects of medications, healthcare treatments, and interventions. The near complete transition to the digital collection of real-world data (RWD) has led to the explosion of interest in observational studies to examine the benefits and harms of medications and other medical interventions. Nevertheless, there has been skepticism by decision makers, especially regulators, regarding the reliability and robustness of the internal validity of observational RWD studies—particularly Hypothesis Evaluating Treatment Effectiveness (HETE) studies (ie, nonrandomized observational studies using existing RWD sets with the intent of testing specific hypotheses regarding treatment effectiveness) and therefore the utility of real-world evidence (RWE) generated by such studies. Much attention has focused on steps to enhance the credibility of RWE through greater rigor in study design, analysis, and transparency in reporting. Although these steps may important across all decision makers, we focus here on ways to enhance the credibility and utility of HETE studies for regulators as part of the totality of evidence rather than other types of RWE (eg, external controls).