RCTs not feasible? Think External Control Arms (ECAs)!

The context: Beyond the Gold Standard

Randomized Controlled Trials (RCTs) remain the gold standard to assess treatment effect. But they are sometimes impractical or even unfeasible, especially in rare diseases or severe oncology indications where assigning patients to a placebo or an outdated Standard of Care (SOC) is unethical, or when patient recruitment is highly challenging.

This has led to a rise in Single-Arm Trials (SATs). However, to prove true therapeutic value, SATs still require a robust external comparator.

The solution: Methodologically Rigorous ECAs

An External Control Arm (ECA) involves constructing a synthetic control group using Real-World Data (RWD). Constructing a regulatory-grade ECA is complex and requires mimicking the design of an RCT to minimize bias:

• Defining the Estimand & Target Trial Emulation: Precisely define the estimand (the causal question) and align the ECA design with the target RCT by replicating the target trial’s Inclusion/Exclusion (I/E) criteria to the ECA and carefully defining the index date to prevent selection bias and immortal time bias.
• Confounding Adjustment: Apply causal inference methods like Propensity Score Matching or Inverse Probability of Treatment Weighting (IPTW) to balance baseline covariates since the treatment assignments are not randomized.
• Diagnostics & Analysis: Evaluating covariate balance and checking statistical assumptions before estimating the treatment effect.
• Sensitivity & Quantitative Bias Analyses (SA & QBA): Stress test findings through robust SA and QBA to quantify the sensitivity to design choices and the potential impact of departures from statistical assumptions.

The trend: Increasing Regulatory and HTA Acceptance

ECAs are increasingly utilized for both regulatory and HTA submissions¹.

Regulators and HTA bodies are actively paving the way with reflections, considerations and guidances on the use of ECAs^2,3,4.

However, the acceptance still remains challenging due to RWD quality issues and methodological flaws⁵.

Our expertise at Quinten Health

We specialize in bridging the gap between RWD and regulatory-grade evidence. From ensuring rigorous RWD processing to deploying robust statistical pipelines, we have successfully accompanied clients across various therapeutic areas. We design transparent, reproducible ECAs to meet the rigorous standards of regulators and HTA bodies.

References

1. Sola-Morales O, Curtis LH, Heidt J, et al. Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions. Clin Pharmacol Ther. 2023;114(2):325-355. doi:10.1002/cpt.2914
2. US Food and Drug Administration (FDA). Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products. January 31, 2023. Accessed June 18, 2026. FDA Guidance Document
3. European Medicines Agency (EMA). Concept Paper on the Development of a Reflection Paper on the Use of External Controls for Evidence Generation in Regulatory Decision-Making. May 21, 2026
4. National Institue for Health and Care Excellence (NICE). NICE real-world evidence framework. June 23, 2022
5. Monnereau M, Delord JP, Michiels S, et al. Acceptance of external control arms by HTA agencies: a review of oncology submissions in France, England, Germany and Norway from 2021 to 2023. Br J Cancer. 2025;133(10):1501-1507. doi:10.1038/s41416-025-03155-6