Since the 21st Century Cures Act passed, real-world data (RWD) and evidence (RWE) have generated significant interest. The Center for Biologics Evaluation and Research (CBER) has received many requests to use RWD and RWE which have presented unique challenges. These challenges include: the quality and extent of documentation of RWE studies, fitness-for-purpose of and access to RWD, and challenges when considering labeling RWE. Documentation of study conduct and analyses is extremely important for RWE, as the study design may require preliminary analyses (subject selection, matching, sample size assessment) and appropriate analyses are complex (confounding adjustment, causal inference). Published RWE studies often lack appropriate documentation, leading to uncertainty about conduct, analyses, and the strength of evidence. RWD fitness-for-purpose and data quality assessments should include statistical considerations, such as access to RWD, limitations imposed by data owners, and sensitivity of analyses to missing data. Labeling presents numerous new difficulties, such as how to estimate relevant treatment effects and adequately convey the sources of uncertainty unique to RWD and RWE.