Real World-Evidence for Regulatory Use Decision Aid: An Interactive Tool To Inform Clinical Development and Regulatory Strategies

This article contains an interactive Decision Aid  to help researchers, industry, and other stakeholders in identifying regulatory situations that can benefit from leveraging real-world evidence. To view it, click here: https://​sn.​pub/​TpDjZx. The interactive Decision Aid can also be accessed through the supplementary material. All files must be extracted for full functionality.

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 [6‐9]. In addition, the currently ongoing COVID-19 pandemic has further reinforced and accelerated Health Authorities’ interest in the potential utility of RWE [10‐12].

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:

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.

Several case examples in which RWE was leveraged to support successful FDA and EMA regulatory submissions were selected and described based on a systematic review of regulatory labels, published literature, and regulatory assessment reports. Each case study was matched with the regulatory objective obtained (new product approval, labeling expansion for new indication or additional clinical data, post-marketing requirement) as well as the type of RWE study design used (external control, observational study, pragmatic trial). Based on this matching, the Decision Aid was organized accordingly by regulatory objective and RWE study design type.

Case studies were assessed for key success factors that have been described in the context of ensuring fit-for-purpose data and rigorous methods, which contributed to a positive regulatory opinion. The assessment was based on a checklist to ensure regulatory-grade data quality (completeness, transparency, generalizability, timeliness, scalability) [14], supplemented by additional considerations around clear endpoint definitions and strategies for minimizing bias for a careful assessment of data quality, reliability, and relevance [2, 15, 16]. Providing clear definitions of primary and secondary endpoints is important to avoid variable documentation of key events potentially influenced by subjectivity. RWD often encompasses a broader spectrum of patients which leads to better generalizability than clinical trials, but potential biases need to be considered and mitigated to allow for adequate interpretation of results. Pre-defined data abstraction, harmonization, and quality monitoring are key markers of quality, integrity, and completeness. Being transparent with Health Authorities around the study design deployed, whether in protocols, analysis plans, or reporting of study results, is another key success factor to allow Health Authorities to rigorously assess the RWE submitted. Leveraging recent and timely RWD ensures the data provide relevant insights around clinical decision-making and adequately reflects the dynamic nature of routine medical practice and treatment use. For data that were intended for scaling, data curation processes, applicability to multiple contexts, and variable definitions were also assessed.

The Decision Aid includes case studies on pharmaceutical products from multiple manufacturers and includes case studies that were available at the time this manuscript was drafted. The authors intend to submit annual updates as the regulatory landscape, frameworks, and case studies change.

The Decision Aid can be accessed at https://​sn.​pub/​TpDjZx.

Users can navigate through the Decision Aid by using sequential multi-step navigation as the tool matches the regulatory objective being evaluated with the corresponding key success factors, the most applicable RWE study types, and real-life precedent cases for reference.

The list of case studies included in the Decision Aid is not exhaustive, as new case studies potentially became available after the tool was developed.

The Decision Aid will help guide pharmaceutical companies and clinical researchers in assessing general appropriateness of a potential RWE approach for use in clinical development within a regulatory context. The Decision Aid does not aim to replace Health Authority guidance or the critical importance of engaging Health Authorities on RWE proposals early on to gather their feedback on the proposed approach, but the tool can help identify potential opportunities for leveraging RWE to inform certain regulatory objectives. It is this identification step that the Decision Aid aims to focus on. Further comprehensive assessment based on the particulars of a situation may be necessary to confirm whether a real-world evidence-based approach for a particular scenario is appropriate.

RWE has been increasingly used in later stages of drug development. Importantly, the intent of RWE is not to replace clinical trials but to apply RWE where appropriate to support drug development and ultimately regulatory submissions. Through identifying and illustrating key aspects of situations where RWE has been utilized for regulatory decision-making, the Decision Aid helps pharmaceutical companies and clinical researchers understand the type of potential evidence necessary for regulatory submissions, adds to the knowledge of available RWE, and encourages further regulatory activity using RWE to pave the way for broader acceptance by clinical researchers, pharmaceutical companies, and Health Authorities. To maximize the chances for success, any research proposal that intends to be used for regulatory decision-making should be discussed with the relevant Health Authority before the research is started.