Real-world evidence (RWE) has traditionally played a relatively limited role in the regulatory process, for example, addressing unmet need and satisfying post-marketing safety monitoring requirements. In the current evolving healthcare landscape, however, there has been a shift towards utilizing RWE in a more central and fit-for-purpose role through identifying situations in which RWE can help establish the clinical effectiveness of a therapy to support regulatory decision-making rather than only to supplement insights from clinical trials [1].

In the US, the Framework for the Food and Drug Administration’s (FDA’s) RWE Program was released in December 2018 and outlines several important RWE-related efforts the Agency is undertaking to evaluate the potential of RWE to support changes to labeling, such as adding or modifying an indication, a change in dose, dose regimen, or route of administration; adding a new population; or adding comparative effectiveness or safety information [2]. In Europe, the European Medicines Agency’s (EMA’s) Regulatory Science Strategy 2025 initiative includes the promotion of high-quality RWE in decision-making to generate complementary evidence across the product lifecycle as one of its five strategic goals [2]. RWE initiatives are being conducted by other global health authorities around the world as well, including in Canada [3], China [4], and Japan [5], to encourage and optimize the use of RWE for regulatory decisions, while focusing on the reliability and quality of evidence. Given the increasing interest in leveraging RWE for regulatory decision-making, there have been many recent publications on insights and recommendations on ways to ensure fit-for-purpose RWE [6,7,8,9]. In addition, the currently ongoing COVID-19 pandemic has further reinforced and accelerated Health Authorities’ interest in the potential utility of RWE [10,11,12].

Despite the growing interest in leveraging RWE by industry and evaluation of RWE by Health Authorities for regulatory decision-making, it is important to note that RWE is not applicable to all situations and should not be considered a replacement for clinical trials [13]. Regulatory acceptance of RWE to support data from clinical trials is subject to the respective Health Authority’s approaches and practices. The authors of this manuscript developed an interactive tool (“Decision Aid”) to assist in more easily identifying circumstances in which the use of RWE informed regulatory decision-making (Figure 1; https://sn.pub/TpDjZx). To date, RWE has been used in certain situations to support new product approvals, label expansions for new indications or additional clinical data, and fulfillment of post-marketing requirements. In such cases, various real-world (RW) or RW-clinical hybrid designs have been utilized, including external controls (external benchmarks or external comparators), observational studies, and pragmatic clinical trials. There are various factors, such as the rarity of the disease, magnitude of treatment effect, availability of quality RWD, and others, that can help inform the appropriateness of a RWE approach for regulatory decision-making. These factors can be better understood by reviewing precedent cases in this space.

The aim of this paper is to describe an interactive Decision Aid designed to:

Serve as a tool for researchers, industry, and other stakeholders to identify areas of opportunity for RWE to support regulatory strategies and clinical development plans.

Illustrate key uses of RWE for regulatory purposes (by utilizing precedent cases where RWE was successfully used to support regulatory decisions), corresponding RWE study designs, and underlying key success factors.

Encourage further use of RWE and activity in this space to add to the growing evidence and establishment of RWE in regulatory submissions.

This article and associated Decision Aid are intended to help researchers identify potential use cases in which RWE might be considered to inform regulatory decision-making.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals.