The pharmaceutical industry is witnessing a significant shift in how drug development and regulatory decisions are made, with Real-World Data (RWD) and Real-World Evidence (RWE) emerging as powerful complements to traditional randomized clinical trials (RCTs). This trend is reshaping the entire product lifecycle from discovery to post-marketing surveillance, offering new pathways to accelerate innovation while maintaining scientific rigor.
Understanding Real-World Data and Evidence
Real-World Data refers to health information collected outside the controlled environment of randomized clinical trials. According to the U.S. Food and Drug Administration (FDA), RWD is defined as "data related to patient health status or delivery of healthcare" from sources such as electronic health records (EHRs), claims databases, disease registries, patient-generated data, and wearable devices.
Real-World Evidence is the clinical evidence derived from analyzing RWD about the usage, potential benefits, or risks of a medical product. While RWD is the raw information, RWE represents the insights and conclusions drawn from this data through appropriate analytical methods.
The characteristics of valuable RWD often align with the "5Vs" framework of big data:
- Volume: Large quantities of data
- Variety: Diverse data types and sources
- Velocity: Speed of data generation and processing
- Value: Meaningful insights that can be extracted
- Veracity: Accuracy and reliability of the data
Regulatory Landscape and Growing Acceptance
The regulatory environment for RWE has evolved significantly in recent years. The 21st Century Cures Act, signed into U.S. law in 2016, marked a turning point by mandating the FDA to develop a framework for incorporating RWE into regulatory decision-making. By 2018, the FDA had issued its framework, providing guidance on using RWD/RWE for supporting changes in indications, dosing regimens, routes of administration, and adding new patient populations.
Similarly, the European Medicines Agency (EMA) announced its vision for enabling RWD/RWE in regulatory decisions by 2025 in its "Regulatory Science Strategy to 2025." Other regulatory bodies worldwide, including those in the UK, China, Taiwan, Singapore, South Korea, Australia, and New Zealand, have either released similar guidance documents or are developing frameworks for RWE utilization.
How RWE Complements Randomized Clinical Trials
While RCTs remain the gold standard for establishing efficacy, they have inherent limitations that RWE can help address:
Larger and More Diverse Sample Sizes
RWE studies can include substantially larger patient populations than typical RCTs, which is particularly valuable for studying rare diseases where patient recruitment is challenging. Currently, only about 5% of rare diseases have approved treatments, making RWE a potentially crucial approach for evaluating orphan drugs.
Efficacy vs. Effectiveness
RCTs excel at demonstrating efficacy under ideal, controlled conditions, but RWE provides insights into effectiveness in real-world practice. This distinction is critical as treatments that perform well in controlled environments may show different outcomes when used in everyday clinical settings with diverse patient populations and varying levels of adherence.
External vs. Internal Validity
RCTs prioritize internal validity through strict inclusion/exclusion criteria, which often exclude patients with comorbidities, extreme ages, or polypharmacy. A literature review of 52 RCTs found that the majority had real-world ineligibility rates greater than 50%, meaning that more than half of actual patients would not qualify for these trials. RWE studies, with their broader inclusion of patient types, offer greater external validity or generalizability to routine clinical practice.
Applications Throughout the Product Lifecycle
Early Drug Development
RWD can identify unmet medical needs, disease burden, and epidemiological patterns to inform research priorities. For example, a cross-sectional study using the Joint Asia Diabetes Evaluation (JADE) register revealed poor glycemic control patterns in Asian populations with diabetes, highlighting specific research needs.
Clinical Trial Design and Execution
RWE can optimize patient recruitment criteria, estimate required sample sizes, and select appropriate surrogate markers. In some cases, RWD can provide historical controls when traditional RCTs are not feasible due to ethical considerations or recruitment difficulties.
Regulatory Approval
Regulatory agencies are increasingly accepting RWE to support new drug applications, particularly in oncology, rare metabolic diseases, and immunology. For instance, Lepirudin received approval in 1998 using registry data as historical controls for patients with heparin-associated thrombocytopenia.
Post-Marketing Activities
RWE plays a crucial role in monitoring safety and effectiveness after market launch. A systematic review found that RWE provided evidence for 59% of safety evaluations and 34% of efficacy assessments in post-marketing referrals in the European Union from 2013-2017.
RWE can also support label expansions and new indications. Between 2012 and 2019, ten products submitted applications for new indications with RWE support to the EMA and FDA. In 2016, Japan approved Raloxifene for osteoporosis based on retrospective analysis of hospital claims data.
Additionally, RWE can inform prescription-to-OTC switches by providing data on patients' ability to self-diagnose, self-medicate, and the economic benefits of such transitions.
Methodological Considerations and Challenges
Despite its potential, RWE faces several methodological challenges:
Confounding and Bias
The lack of randomization increases the risk of confounding variables and selection bias. Researchers employ various strategies to address these issues, including:
- Statistical methods like propensity score matching
- Using proxy measurements for unmeasured confounders
- Implementing self-controlled designs and sensitivity analyses
- Utilizing instrumental variables
Data Quality and Standardization
Many RWD sources were not designed for research purposes, leading to issues with missing data, transcription errors, and inconsistent terminology. International initiatives like the Observational Health Data Sciences and Informatics (OHDSI) are working to transform medical data into consistent formats for research.
Privacy and Security Concerns
RWD often contains sensitive personal information, raising privacy concerns when databases are linked for analysis. Regulations like the General Data Protection Regulation (GDPR) in Europe govern data collection, storage, and sharing. Advanced security measures, including data encryption, k-anonymization, differential privacy, and role-based access controls, are essential for protecting patient information.
The Hong Kong Perspective
In Hong Kong, RWE studies have increased significantly since the implementation of the electronic health record (eHR) system in 2016. A notable example is a 2022 retrospective cohort study on COVID-19 antivirals (molnupiravir and nirmatrelvir-ritonavir) that analyzed data from 40,000 hospital inpatients, providing timely evidence in just eight months.
The use of eHR data in Hong Kong is protected under the Electronic Health Record Sharing System Ordinance (Cap. 625) and Personal Data (Privacy) Ordinance (Cap 486). While the Hospital Authority provides access to clinical data for universities through the Clinical Data Analysis and Reporting System (CDARS), access for pharmaceutical companies is still developing.
Hong Kong aims to become a world-leading biotechnology data hub, but this will require strengthening health data infrastructure and promoting academic-industry collaboration while balancing data availability with privacy protections.
The Role of Pharmacists in the RWE Era
As RWE becomes more prevalent, pharmacists face growing responsibilities in interpreting and evaluating this evidence for clinical decision-making. When assessing RWE studies, pharmacists should:
- Evaluate the relevance of the research question using frameworks like PICOT (Population, Intervention, Comparator, Outcome, Timing)
- Assess the validity of the study design
- Examine the quality and completeness of the data
- Look for descriptions of data collection, cleaning, and transformation processes
Pharmacists also contribute to RWE generation through their domain expertise and by ensuring accurate data entry in clinical practice, recognizing that routine documentation may later become valuable research data.
Future Directions
The future of RWD and RWE in pharmaceutical R&D looks promising, with increasing interdisciplinary collaboration across the pharmaceutical industry, regulatory bodies, nonprofits, and health policy stakeholders. As methodologies mature and data quality improves, RWE will likely play an even more significant role in accelerating innovation while maintaining scientific rigor.
The global expansion of RWE requires harmonization of data access across geographic regions to ensure insights derived in one area can benefit patients worldwide. Strategic frameworks or "roadmaps" for RWE integration throughout product lifecycles are being developed to address challenges in data collection standardization while maximizing the potential benefits of real-world insights.
As this field continues to evolve, balancing innovation with scientific validity and patient privacy will remain essential priorities for all stakeholders in the pharmaceutical R&D ecosystem.
