REAL-WORLD EVIDENCE: GAINING MOMENTUM IN CLINICAL RESEARCH

Real-World Evidence: Gaining Momentum in Clinical Research

Sidney Lane, PhD
Clinical and Regulatory Affairs Project Lead
, Clinical Research Strategies

December 2024

Traditional randomized controlled trials (RCTs) are regarded as the gold standard in clinical data generation. However, RCTs only have approximately 10% likelihood of commercial success for interventional therapies(1), reflecting stalled progress in patient care and an abysmal return on investment for stakeholders. Several factors contribute to this low success rate(2), notably the restrictive nature of RCTs, which are often conducted in limited patient populations and controlled environments that do not reflect everyday clinical practice.

To address these limitations, regulatory authorities are focused on expanding evidence generation to include real-world evidence (RWE). RWE consists of data collected as part of routine healthcare, providing valuable insights into treatment effectiveness and patient outcomes in diverse real-world settings. By integrating RWE, we can bridge the gap between clinical research and clinical practice, enhancing our understanding of therapies in real-world scenarios.

RWE: Past and Present

The US Food and Drug Administration (FDA) defines RWE as “clinical evidence regarding the usage and potential benefits or risks of a medical product via analysis of real-world data (RWD)” with RWD defined as “data relating to patient health status and delivery of healthcare routinely collected from various sources.” RWD includes data generated from electronic health records (EHRs), routine clinical practice, patient registries, claims databases, and other sources outside the controlled environment of an RCT. When RWD is collected and analyzed as part of a non-interventional study design, it has the potential to lead to the generation of RWE which has many uses, such as market access, reimbursement, safety surveillance, removal of cautions or warnings, label expansion, and/or regulatory decision-making.

Historically, RWE has primarily been utilized for post-market safety surveillance, registries and other phase 4 trials, and for obtaining special designations for medical products, particularly for indications of oncology and rare diseases. The 21st Century Cures Act, enacted in 2016, initiated a federal effort to broaden the use of RWE in clinical studies, resulting in a substantial increase in RWE applications and regulatory frameworks. It is reported that between 2019-2021, the number of FDA-approved applications containing RWE increased from 75% in 2019 to 96% in 20213. Since the Cures Act, the FDA has released ten guidances on the use of RWE in clinical trials, including three released in 2023 and one released in 2024, underscoring the FDAs commitment to integrating RWE. Throughout these guidances, the FDA has maintained a consistent emphasis on quality (data sources are relevant, reliable, and robust), effective study design (appropriate to generate reliable RWE), stakeholder engagement (continued collaboration between industry, academia, and regulators as the RWE landscape evolves), and regulatory use (permitting RWE as evidence for a variety of approvals).

As RWE gains broader acceptance, its applications have expanded significantly. RWE is now increasingly accepted as supportive evidence for label expansion and modification, new drug and device applications for a wider range of indications, and beyond special designations. Further, RWE studies are now being employed earlier in the clinical trial pipeline and are often conducted alongside RCTs to generate data on the endpoints observed in the RCTs across a broader population earlier in the life cycle of the product.

Prominent examples include the FDA’s 2018 approval of the Hemospray Endoscopic Hemostat (DEN170015), where RWE from a registry study and two observational studies acted as the sole clinical evidence for this successful de novo application. Similarly, in 2023, the FDA approved the Biological License Application (BLA) for IXCHIQ (BL 125777/0 [PDF file]) (VALNEVA Austria GmbH), a chikungunya virus vaccine, in 2023. IXCHIQ was approved under Accelerated Approval designation based on clinical data from three interventional studies and the Sponsor’s proposed post-market confirmatory RWE studies, which will run concurrently with their subsequent pragmatic RCTs.

Other regulatory bodies are also developing RWE guidance and frameworks. In 2023, Health Canada released the Guidance for Reporting Real World Evidence4 which laid the foundation for use of RWE for regulatory approval and standardized reporting of RWE. The European Medicines Agency (EMA) recently established an online RWD repository of observational data sources from EU hospitals and healthcare centers, known as Data Analysis and Real World Interrogation Network (DARWIN)5, and the EMA is expected to release an updated RWE regulatory guidance in 2025. Additionally, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) addresses RWE in Annex 2 of the upcoming E6(R3) Guideline for Good Clinical Practice (GCP). The draft for Annex 2 [PDF file] was released for public consideration in November 2024.

Table 1 represents prominent regulatory authorities who have begun to enable discussion for RWE and it is expected that others will defer to these authorities for adoption.