Adding Real-World Evidence to a Totality of Evidence Approach for Evaluating Marketed Product Effectiveness

This paper responds to growing interest in using real-world data (RWD) and real-world evidence (RWE) in regulatory decision-making. In comparison with randomized controlled trials (RCTs), RWD has the potential to provide more representative information on a therapy’s impact in a broader patient population, capture the evolving standard of care, and better reflect routine clinical care. With the increased curation of relevant and reliable RWD, and with the development of advanced analytical methods to make valid causal inference, RWE has the potential to complement the evidence generated from RCTs and to fill evidentiary gaps for healthcare decision-making. Because of this potential, the 2018 Framework for FDA’s Real-World Evidence Program called for exploration of the use of RWE and RWD for regulatory decision-making regarding the effectiveness of marketed products. When seeking an original approval by the U.S. Food and Drug Administration (FDA) for a product, an evidence package generally contains three types of studies: clinical pharmacology, non-clinical toxicology, and clinical studies. During subsequent effectiveness labeling changes (for example, use in a new population or adding or modifying an indication), the evidence package includes the prior submitted evidence and new evidence, which often consists of clinical studies only. Traditionally, these clinical studies were in the form of RCTs; however, this paper explores how RWE studies may contribute to an evidence package. Regardless of study type, setting, or design, FDA does not evaluate one study only when making regulatory decisions. Instead, FDA uses a totality of evidence approach, examining all available evidence in the package including the quality of the studies and the clinical and regulatory contexts. Multiple factors inform the weighting that is assigned or degree to which each piece of evidence contributes to the regulatory decision. Therefore, this paper discusses how an evidence package including RWE can contribute to substantial evidence within a totality of evidence approach to inform an effectiveness labeling change. To illustrate how RWE can fill evidentiary gaps and contribute to the evidence package, case studies for existing marketed products and hypothetical case studies were reviewed through the lenses of the clinical and regulatory contexts.