Real-World Data (RWD) is being increasingly utilized in clinical research to help support drug approvals. The U.S. Food and Drug Administration (FDA) guidance on Considerations for the Use of Real-World Data and Real-World Evidence (RWE) to Support Regulatory Decision-Making for Drug and Biological Products provides thoughtful recommendations on the use of RWE to support approval of a new indication for marketed drugs. This guidance is part of the FDAs Real-World Evidence Program which provides additional guidance for the use of RWE to support regulatory decisions. While RWD and RWE are related, it’s important to understand the distinction between the two. Real-World Data captures data from real-world healthcare settings and can be collected from a variety of sources where RWE is the clinical evidence generated from the analysis of RWD.

This guidance document focuses on non-interventional studies, which can be defined as observational studies where patients receive the marketed drug of interest as part of their standard care from their medical provider. Below is a summary of topics to consider when designing a study utilizing RWD to provide RWE in support of regulatory decisions.

Considerations for selection of the RWD source:

• The data source should be evaluated to ensure the database contains information that addresses the research question of interest.
• The statistical precision of the data should be estimated without formally evaluating endpoints of interest.
• Confirm the patient-level data can be submitted to FDA through traditional channels or the third-party vendor can provide data to the FDA through existing third-party regulatory pathways.
• Confirm source data can be made available to the FDA for inspection.

Documentation considerations for studies utilizing RWD:

• The protocol should describe the data sources evaluated, results from feasibility evaluations, and any exploratory analyses performed during the selection process. Additionally, the Sponsor should describe how the final data source and analytic approach were selected to ensure they do not favor a particular study finding.
• The final study report should describe the patient characteristics of the source data and the study population (i.e., those included in analyses) and note any differences that may impact study findings.

Recommendations in common with interventional trials:

• The protocol and statistical analysis plan (SAP) should be provided to the Agency for review prior to finalization and conducting analyses.
• The study protocol should be posted on a publicly available website (e.g., ClinicalTrials.gov).
• The final study report should clearly state which analyses were pre-specified in the SAP and which were exploratory.
• Any deviations from the pre-specified protocol and SAP are identified and documented.
• The principles of data quality apply after extraction of the RWD. This includes maintaining an audit trail, tracking user access, data changes, etc.
• In addition to submission of the patient-level data to the FDA, associated programming code and algorithms should be provided to the FDA for replication of analyses.

Heather Kopetskie, Senior Director, Biostatistics, has worked at Rho for more than 19 years. Ms. Kopetskie provides leadership and oversight for the biostatistics department and utilizes her experience to guide sponsors on the design and analysis of clinical trials. Her experience spans many therapeutic areas with an emphasis on solid organ and cell transplantation along with rare disease (orphan) products. Ms. Kopetskie has supported both federally funded projects and biotech/pharmaceutical companies. She has served as the biostatistical functional lead for the Immune Tolerance Network (ITN) Statistical and Data Coordinating Center and the Clinical Trials in Organ Transplantation (CTOT) Statistical and Clinical Coordinating Center overseeing more than 30 studies in the areas of allergy, immunology, and transplantation.