FDA on Real-World Data for Clinical Trial Regulatory Safety Studies

The 2024 DIA conference held a session on Harnessing Real-World Data to Generate Real-World Evidence for Clinical Trial Regulatory Safety Studies, which provided significant insights into the evolving landscape of pharmacoepidemiology and therapeutic risk management. Chaired by Dr. Alicia Gilsenan, Vice President of Epidemiology at RTI Health Solutions, the DIA session featured expert presentations from Dr. Marie Bradley, Senior Advisor at the FDA, and Dr. Angelika Manthripragada, Director at Regeneron. This session delved into the practical applications of real-world data (RWD) in regulatory safety studies, showcasing use cases and discussing methodological challenges.

Keynote by Dr. Alicia Gilsenan

Dr. Alicia Gilsenan emphasized the growing importance of RWD in clinical trials and clinical trial regulatory submissions. Although not a new concept, integrating RWD earlier in clinical trials is becoming more common, reflecting broader acceptance and reliance on comprehensive safety and effectiveness data that traditional trials might miss. Dr. Gilsenan explained pharmacoepidemiology, highlighting the International Society of Pharmacoepidemiology (ISPE) and its role in advancing the field through resources and annual meetings.

Dr. Gilsenan shared her experience with long-term observational studies on teriparatide, a drug for osteoporosis initially flagged with a black box warning due to osteosarcoma risk. Over 18 years, four studies were conducted, including a case series study, a prospective registry study enrolling 75,000 patients, and two using Medicare and commercial claims data linked with state cancer registries. These efforts led to the removal of the black box warning in 2020. Another example was prucalopride, a chronic constipation drug approved in Europe in 2009 but requiring additional cardiovascular safety data for US approval. Utilizing European RWD, the company demonstrated no increased risk, leading to US approval with study results in the drug’s labeling.

Dr. Marie Bradley on FDA’s Real-World Evidence Framework

Dr. Marie Bradley detailed the FDA’s framework for evaluating RWD under the 21st Century Cures Act, designed to support new drug indications and fulfill post-approval study requirements. The program, formalized in 2018, includes internal processes, external stakeholder engagement, and research projects addressing methodological gaps. The FDA’s Real-World Evidence Subcommittee invites senior leadership and external experts to provide insights on RWD submissions.

Dr. Bradley highlighted the Sentinel System’s use for post-market safety assessments, covering over 100 million lives. Notably, during the COVID-19 pandemic, it monitored drug utilization and safety, proving essential in public health emergencies. Despite its success, challenges remain, such as needing more flexible tools and integrating additional EHR data. The FDA’s Sentinel Innovation Center aims to enhance system capabilities, especially for complex pharmacoepidemiologic safety assessments. Key considerations for using RWD in clinical trial regulatory studies include ensuring data fit, understanding the limitations of different sources, and selecting appropriate study designs. Early and frequent FDA consultations are crucial for aligning expectations and methodologies.

Dr. Angelika Manthripragada on Real-World Data in Ophthalmology

Dr. Angelika Manthripragada presented an RWD case study to assess aflibercept, an anti-VEGF treatment for retinal diseases. The study focused on the risk of intraocular inflammation (IOI), comparing pre-filled syringes and vials. Aflibercept, administered intravitreally, treats conditions like age-related macular degeneration (AMD) and diabetic macular edema (DME). The pre-filled syringe, introduced to reduce contamination risk, was hypothesized to lower IOI risk.

The analysis involved spontaneous reporting data from global post-marketing safety surveillance and an observational study using the Vestrum Health Retina Database. Spontaneous reporting showed a lower IOI rate with pre-filled syringes (0.003 cases per 100 units) versus vials (0.012 per 100 units). Regeneron conducted an observational study to quantify risk, including over 2 million aflibercept injections from 2014-2022, confirming lower IOI incidence with pre-filled syringes. The Vestrum database, chosen for its comprehensive retinal specialist data, was crucial for accurate IOI assessment. Combining data sources provided robust safety insights, emphasizing the need for ongoing RWD surveillance in safety monitoring.

Panel Discussion and Q&A

The session concluded with a panel discussion, where speakers addressed audience questions on integrating RWD from different sources, data quality, and methodological issues. Dr. Bradley emphasized data relevance and reliability, highlighting the FDA’s efforts to integrate more EHR data into the Sentinel System and enhance data accuracy and completeness through research projects. She noted that the Sentinel System reduces sponsors’ post-approval study burdens, although flexibility remains challenging.

Dr. Manthripragada discussed the implications of the aflibercept study for other injectable drugs, emphasizing the need for context-specific assessments. She described using control cohorts to compare adverse event incidence across different populations or treatment modalities. The panelists stressed early and continuous regulatory engagement. Dr. Gilsenan reiterated the importance of collaborating with industry, academia, and regulators to design and conduct RWD studies that meet clinical trial regulatory standards and provide valuable safety insights.

Conclusion

The conference session highlighted the transformative potential of RWD in enhancing clinical trial regulatory safety assessments. The speakers demonstrated how RWD can effectively support regulatory decisions and improve patient safety by providing real-world examples and addressing practical challenges. As the field continues to evolve, ongoing collaboration and methodological advancements will be essential to fully harness the power of RWD in clinical research and regulatory science.