Regulatory and HTA Considerations for RWD-Derived External Controls
This guideline outlines best practices for using real-world data to create external control groups in clinical studies, especially when no internal control group is available. It emphasizes the need for careful design and alignment with regulators and HTA bodies to ensure the resulting evidence is trustworthy and useful for decision-making.
At a glance
Use when
Designing uncontrolled trials where external controls are needed; preparing regulatory or HTA submissions using real-world evidence; planning RWD studies for comparative effectiveness
Avoid when
When high-quality randomized controlled trial data are available; when real-world data sources are known to be highly biased or incomplete; in absence of stakeholder alignment on methodology
Inputs
Real-world data (e.g., electronic health records, registries), uncontrolled clinical trial data, regulatory and HTA requirements
Outputs
Fit-for-purpose real-world evidence from external control studies suitable for regulatory and HTA submissions
How it works
The guideline builds on a systematic literature review of real-world data (RWD)-derived external controls used in submissions to the EMA, FDA, and selected HTA bodies. It identifies six key methodological and operational considerations: early engagement with regulators and HTA bodies; ensuring comparability of external controls across eligibility, timing, population, and clinical factors; adequate sample size and hypothesis testing; transparent data quality assessment including handling missing data; selection of appropriate and comparable endpoints with valid analytical methods; and performance of sensitivity analyses to evaluate robustness against bias and uncertainty.
- HTA domains
- Clinical Effectiveness, Costs & Economic Evaluation, Safety
- Assumptions
- Real-world data can be sufficiently comparable to clinical trial populations when carefully selected and adjusted; early stakeholder engagement improves study validity and acceptance
- Strengths
- Provides actionable, evidence-informed guidance aligned with current regulatory and HTA practices; addresses both methodological and operational aspects; promotes transparency and robustness through sensitivity analyses and data quality strategies
- Limitations
- Does not provide detailed statistical protocols or software tools; applicability may vary across jurisdictions and data sources; dependent on data availability and quality
- Also known as
- RWD-derived External Controls Guideline, Real-World Data External Controls Framework
Questions this answers
- › How can real-world data be responsibly used to create external control groups in uncontrolled trials?
- › What are the key methodological challenges in using RWD-derived external controls?
- › How can comparability between trial patients and external controls be ensured?
- › What role does early engagement with regulators and HTA bodies play in study design?
- › How should data quality and missingness be addressed in RWD-derived control studies?
- › What types of sensitivity analyses are recommended to test the robustness of results?
References & sources
Similar by meaning
Beta record. Based on the original catalogue summary; primary-source enrichment pending.