Standards for external control arms built from federated real-world data
When a trial has no comparison group, the comparison is sometimes built from old patient records. Set rules for how that is done so the answer is not rigged.
External control arms from real-world or historical trial data are increasingly used in rare cancers and single-arm approvals, with inconsistent methods. The proposal defines standards: pre-specification before trial unblinding, construction from federated data with documented eligibility mapping, minimum covariate set, quantitative bias analysis and tipping-point sensitivity analyses, plus public deposition of the control cohort definition. Regulatory guidance (FDA 2023 draft on externally controlled trials) is the starting point.
- Weak real-world evidence and registries · We do not reliably know what happens to patients after approval, so we cannot tell which drugs deliver in practice.
- Trial design, endpoints and cost · A phase 3 trial takes years and hundreds of millions of dollars, and often answers a question that has already moved on.
- Rare and paediatric cancers without markets · Taken together rare cancers are a fifth of all cancers, but each one alone is too small for a company to invest in.
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