Regulatory Submissions with Real-World Evidence: Highlights from the Joint Duke Margolis Institute and FDA Public Meeting

As Real World Evidence (RWE) becomes an increasingly important component of the totality of evidence generated for medicines and devices, regulatory bodies continue to develop and evolve guidance and frameworks to help sponsors strategically incorporate RWE to support safety and efficacy/effectiveness. To streamline this process for sponsors, the US FDA developed a framework for evaluating the use of RWE, which included the launch of the FDA Advancing RWE program.

The Advancing RWE program was established in 2022 with three goals:

• Identify approaches for generating RWE that meet regulatory requirements in support of labeling for effectiveness
• Develop agency processes that promote consistent decision-making and shared learning regarding RWE
• Promote awareness of characteristics of RWE that can support regulatory decisions by allowing FDA to discuss study designs considered in the Advancing RWE Program in a public forum.

On September 23^rd, the Duke Margolis Institute for Health Policy convened a public meeting in conjunction with the US FDA on the topic of Regulatory Submissions with Real-World Evidence (RWE): Successes, Challenges, and Lessons Learned, with over 4,000 virtual and in-person attendees. This meeting completes the FDA's 2025 RWE-PDUFA VII commitments for the Advancing RWE program and included case studies with a focus on how to generate RWE for regulatory requirements. By the end of 2026, the FDA will use lessons learned from their Advancing RWE Program to update existing, or generate new, RWE-related guidance documents.

In opening remarks, Dr. Sarah Brenner, Principal Deputy Commissioner at the FDA, described ongoing efforts in RWE as part of the path toward a "more modern and agile FDA." Modernization and agility were repeated themes throughout the day.

Another theme was the importance for sponsors to engage with the agency early as a thought partner in study design, to determine the best way to incorporate RWE. According to sponsors presenting case studies, this approach was one of their biggest success factors. Case studies presented largely focused on data source fitness for use, appropriateness of the RWE study design, and regulatory considerations, which is consistent with current guidance.

The panel session focused on the strengths and challenges of using RWD. Panelists were from Office of Medical Policy, CBER, Abbott, Orchard Therapeutics, and Bristol Myers. The panel spoke on a number of topics including data source selection and fitness for use:

• The agency does not endorse any particular data source and is open to considering any data source that meets requirements, including natural history studies, registries, EHRs, claims, hospital charge master data.
• Data feasibility studies^a are required to understand relevance and reliability of the data, data quality, and population fit.
• The data source(s) should contain the outcome or exposure of interest, and outcomes should be objective (e.g., overall survival).
• The data source should have enough patients for the study.
• Robust sensitivity analyses are needed on endpoints to test assumptions on relevance and reliability of the data.
• When there is limited of data, such as with ultrarare diseases, natural history^b cohorts become very important for direct comparisons.

When the topic of broader use of RWE came up, beyond unmet need and into more general diseases, there was tempered optimism among the panel. The field is evolving, and there is some expectation that the use of RWE will become much more common, including greater use in registrational trials,^c post-marketing requirements (PMRs), and post-marketing commitments (PMCs). While there is more bias potential in observational studies than in controlled trials, but with larger sample sizes (e.g., in more general diseases), sponsors may be able to design studies better and include more complex analyses to minimize bias. However, it was clear that the continued expectation is that the role of RWE is to complement, not replace, controlled trials.

Sponsors and regulators agreed that they are all invested in seeing greater use of RWE in the future. Accordingly, the agency has new efforts underway to look at methods to promote alignment and consistency. Ultimately, the FDA is looking to lead efforts to advance the field globally.

Additional resources:

1. To learn more about data source feasibility assessments, read UBC's recently posted blog on this topic, titled "Is Your Real-World Data 'Fit-for-Purpose'? The Critical Role of Feasibility Assessments."
2. To learn more about Natural History Studies, read UBC's white paper, "Understanding the Natural History of Disease."
3. To learn more about linking real-world data to clinical studies, read UBC's publications:

• Case study: Enriching clinical studies with longitudinal real-world data
• White paper: Gain Strategic Insights by Linking Clinical Trial Data to Real World Data
• Blog: Longitudinal Real-World Data: How to Gain Deeper Insights Into Your Clinical Studies
• Blog: RWD Enrichment Studies: Linking Pre- and Post-Trial Data Utilizing Tokenization

About UBC
United BioSource LLC (UBC) is the leading provider of evidence development solutions with expertise in uniting evidence and access. UBC helps biopharma mitigate risk, address product hurdles, and demonstrate safety, efficacy, and value under real-world conditions. UBC leads the market in providing integrated, comprehensive clinical, safety, and commercialization services and is uniquely positioned to seamlessly integrate best-in-class services throughout the lifecycle of a product.

About the Author

Judy Lytle, PhD, MBEE, PMP. Executive Director, Evidence Development Study Solutions

Judy Lytle serves as the Executive Director of Evidence Development Study Solutions for UBC. Dr. Lytle joined UBC in 2023, bringing more than 15 years of experience in life science and healthcare strategy development, implementation, and execution. With a background in medical affairs and real-world evidence, she brings together differentiated study design and evidence generation solutions for value demonstration. She also has oversight of epidemiology, patient and physician services, scientific/clinical strategy, and medical writing teams.

Dr. Lytle holds a PhD in Neuroscience from Georgetown University as well as a Master of Biotechnology Enterprise & Entrepreneurship (MBEE) from Johns Hopkins University. A fellow of the American Association for the Advancement of Science (AAAS), and certified Project Management Professional (PMP), her approach is systematic and grounded in science.

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