FDA Finalizes Guidance on Real-World Evidence in Drug Approvals

Key Points

• The FDA has finalized guidance for industry on using real-world data (RWD) and real-world evidence (RWE) to support regulatory decisions for drugs and biologics
• The guidance provides recommendations for data access, safety monitoring, and appropriate use of RWE throughout the drug lifecycle
• This development represents a significant step in expanding the use of real-world data in regulatory decision-making

The U.S. Food and Drug Administration (FDA) has finalized its long-awaited guidance for industry on the use of real-world data (RWD) and real-world evidence (RWE) in supporting regulatory decisions for drugs and biologics. Released on August 23, 2023, the guidance document, titled "Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products," offers pharmaceutical companies and researchers comprehensive recommendations for data access and safety monitoring when leveraging real-world data.

This finalized guidance represents a significant milestone in the FDA's RWE Program, which was launched in 2018 to fulfill mandates under the 21st Century Cures Act. The guidance aims to help support approval of new indications for drugs already approved under section 505(c) of the FD&C Act or to support post-approval study requirements.

Framework for Evaluating RWD and RWE

The guidance document provides a structured framework for evaluating whether real-world data are fit for use in regulatory decision-making. It emphasizes the importance of data quality, relevance, and reliability, and outlines considerations for different types of data sources, including electronic health records, claims data, registries, and patient-generated health data.

"This guidance marks a significant step forward in our efforts to facilitate the appropriate use of real-world evidence in regulatory decision-making," said FDA Commissioner Robert M. Califf, M.D. "By providing clear recommendations on how to evaluate and use real-world data, we aim to enhance the evidence base for regulatory decisions while maintaining our commitment to ensuring the safety and effectiveness of medical products."

The guidance emphasizes that the agency will assess RWE based on whether the real-world data are fit for purpose, whether the trial or study design provides adequate scientific evidence to answer regulatory questions, and whether study conduct meets FDA regulatory requirements.

Key Recommendations for Sponsors

The final guidance includes several key recommendations for sponsors interested in using RWE to support regulatory submissions:

• Study Design Considerations: The guidance outlines appropriate study designs for RWE studies, including randomized trials using real-world data sources and observational studies. It emphasizes the importance of pre-specifying the study protocol, statistical analysis plan, and data sources before conducting analyses.
• Data Elements and Quality: Sponsors should ensure that their RWD sources contain adequate information on exposure, outcomes, and potential confounders. The guidance recommends thorough data validation procedures and transparency in reporting data quality issues.
• Documentation Requirements: The FDA expects comprehensive documentation of data sources, collection methods, validation procedures, and analytical approaches. This documentation should be sufficient to allow for the reproducibility of study results.
• Regulatory Interactions: The guidance encourages early and frequent engagement with the FDA when planning to use RWE in regulatory submissions, emphasizing the benefits of discussing study designs and data sources before initiating research.

Additionally, the guidance provides specific considerations for different regulatory contexts, such as effectiveness determinations, safety assessments, and fulfilling post-marketing requirements.

Advancing RWE Program (2023-2027)

In conjunction with the finalized guidance, the FDA has launched an "Advancing Real-World Evidence Program" that will be conducted during fiscal years 2023 to 2027. This program fulfills a commitment under the Prescription Drug User Fee Act (PDUFA) VII and includes a new mechanism for identifying approaches to generate RWE that meet regulatory requirements in support of labeling for effectiveness.

The program also includes a commitment to publicly report on RWE submissions to CDER and CBER starting in 2024. To promote awareness of RWE characteristics that can support regulatory decisions, study designs discussed through the program may be presented by FDA in public forums such as guidance or workshops.

"The Advancing RWE Program represents a significant opportunity for sponsors and the FDA to collaboratively explore innovative approaches to generating high-quality real-world evidence," said Patrizia Cavazzoni, M.D., director of the FDA's Center for Drug Evaluation and Research. "By providing a structured framework for these discussions, we hope to foster innovation while ensuring that real-world evidence used in regulatory decision-making meets the same standards of quality and reliability as other forms of evidence."

Industry and Expert Reactions

The pharmaceutical industry and pharmacoepidemiology experts have largely welcomed the finalized guidance, noting that it provides much-needed clarity on the FDA's expectations regarding RWE.

"The finalized guidance represents a significant step forward in enhancing the use of real-world evidence in drug development and regulatory decision-making," said Jennifer Graff, Chief Development Officer at the National Pharmaceutical Council. "By providing clear recommendations on data quality, study design, and documentation requirements, the FDA has created a pathway for the appropriate use of RWE that can complement traditional clinical trials and potentially accelerate patient access to innovative therapies."

Academic experts in pharmacoepidemiology have also responded positively to the guidance, though some note that challenges remain in implementing the recommendations.

"The FDA's guidance provides a robust framework for evaluating real-world evidence in regulatory contexts," said Dr. Sebastian Schneeweiss, Professor of Medicine and Epidemiology at Harvard Medical School. "However, ensuring data quality and addressing confounding in observational studies remain significant challenges. The success of this initiative will depend on continued methodological innovation and collaboration between regulators, industry, and academia."

Implications for Pharmacoepidemiology

The finalized guidance and the Advancing RWE Program have several important implications for the field of pharmacoepidemiology:

• Methodological Standards: The guidance establishes clear expectations for methodological rigor in RWE studies, which may lead to greater standardization of approaches in pharmacoepidemiological research.
• Data Infrastructure: The emphasis on data quality and validation may accelerate investments in improving healthcare data infrastructure and interoperability.
• Workforce Development: The expanding role of RWE in regulatory decision-making will likely increase demand for skilled pharmacoepidemiologists who can design and conduct compliant studies.
• Collaborative Research: The guidance may foster greater collaboration between pharmaceutical companies, academic researchers, and data partners to generate high-quality RWE.

Furthermore, the guidance's emphasis on transparency and reproducibility aligns with broader trends in scientific research toward open science practices.

Looking Ahead

The finalized guidance and Advancing RWE Program represent significant milestones in the FDA's efforts to integrate real-world evidence into regulatory decision-making. However, several questions and challenges remain to be addressed in the coming years:

• How will the FDA's approach to evaluating RWE evolve as new data sources and analytical methods emerge?
• What role will artificial intelligence and machine learning play in generating and analyzing real-world evidence?
• How will international regulatory agencies harmonize their approaches to RWE, given the global nature of drug development and pharmacovigilance?
• What additional guidance may be needed to address specific therapeutic areas or vulnerable populations?

As the FDA begins implementing the Advancing RWE Program and accumulating experience with RWE submissions, further refinements to regulatory expectations and best practices are likely to emerge.

For now, pharmaceutical companies and researchers in pharmacoepidemiology should carefully review the finalized guidance and consider how to integrate its recommendations into their RWE generation strategies and research protocols.