On International Clinical Trials Day, the UK’s MHRA unveiled a major shift: a consultation on using external control arms (ECAs) based on real-world data (RWD) for regulatory decisions. This move aims to leverage patient-level data collected outside clinical studies to compare the efficacy and safety of interventions in clinical trials. Stakeholders have until the end of June to weigh in.
What’s the Focus?
The guidelines target sponsors planning to use RWD ECAs in trials needing regulatory approval. But the principles also apply to external controls from other sources, like past clinical trials. Notably, the guidelines don’t cover:
- RCTs mainly using RWD for selecting, randomizing, or following up participants.
- Synthetic or virtual control arms with simulated patient data.
- In silico trials using computer modeling instead of real patients.
Key Takeaways
- RCTs Still Reign Supreme: While RCTs are preferred, the MHRA is open to RWD ECAs if the data in the submission is convincing. They’re especially useful when RCTs are unethical, unfeasible, or would cause significant delays.
- Quality Matters: The strength of evidence from RWD ECAs hinges on the quality of the external data source. Sponsors must justify their choice and address bias issues.
- Suitability of Studies: RWD ECAs are more suitable for trials where an internal RCT arm is unethical or unfeasible, like severe diseases with no effective standard of care. They can also augment underpowered RCTs, which may allow for additional secondary endpoints.
- Protocol Considerations: Justify your data sources and methods for constructing the ECA. Match populations based on inclusion / exclusion criteria and address potential biases. Concurrent data collection for RWD is ideal, but the MHRA are not prescriptive on the timing of RWD collection.
- Bias – The Elephant in the Room: Minimize bias by ensuring the ECA is as similar as possible to the single-arm trial. This includes matching patient populations (examine inclusion/exclusion criteria), important baseline characteristics, and timing of key efficacy assessments. Identify RWD sources before the trial starts to align trial design with the features of the external dataset.
More information is in the consultation here.
