The Trouble with Comparators: Fixing External Control Arms with Trial Emulation

Real-world evidence is becoming central to regulatory and HTA decision-making in rare diseases and it is so for good reason. In many rare conditions, the traditional randomized controlled trial (RCT) is simply not feasible. Recruitment is slow. Placebos may be unethical. The patient population is heterogeneous and geographically dispersed. As a result, external control arms (ECAs) built from real-world data (RWD) are increasingly used to supplement or replace comparative arms in single-arm trials.

But not all ECAs are created equal. While regulators and HTA bodies have shown openness to these approaches, their acceptance hinges on how the ECA is designed, specified, and aligned with trial goals. There is guidance on these topics issued by the stakeholders but it is becoming increasingly clear that Target Trial Emulation (TTE) provides a critical framework to implement ECAs correctly. The increase in use of TTE can be observed in the third EMA report on the use of real world evidence in decision making.

Why TTE Matters for External Controls

TTE offers a structured approach to designing observational studies that approximate the design of a randomized trial. For ECAs, it forces sponsors to ask: If we were running a trial with both arms, what would that look like?

This helps address three common failures in external control generation:

🔹Mismatched populations

🔹Poorly aligned timing or follow-up

🔹Unmeasured differences in care pathways or baseline risk

TTE formalizes design choices and provides a transparent protocol that aligns with trial methodology, increasing the chances that regulators and HTAs will view the comparison as credible.

What Makes an ECA Emulation-Ready?

1. A clearly specified hypothetical trial You need a well-defined protocol: inclusion/exclusion criteria, treatment assignment logic, outcome definitions, and duration of follow-up. For example, in a rare metabolic disorder with a single-arm Phase II trial, the emulated arm must mirror key aspects of the trial, including diagnostic criteria and time from diagnosis to treatment.

2. Fit-for-purpose data This remains a major barrier. Many RWD sources lack the resolution needed to construct a valid comparator group. Are lab values available? Is time of diagnosis or symptom onset reliably captured? Is disease severity documented at baseline? If not, the external control may introduce more questions than answers.

3. Temporal and clinical alignment Data from patients treated a decade ago, under different standards of care, may not be comparable, even if the same endpoints are measured. TTE encourages use of contemporaneous cohorts and emphasizes matching on treatment context. For example, a real-world ECA for a gene therapy in a neurodegenerative disease must account for recent shifts in supportive care and diagnostics.

4. Transparency and documentation The strength of TTE lies not just in the analysis but in the design logic. Sponsors must document how the ECA was constructed, including inclusion/exclusion decisions, analytic choices, and handling of missing data. Pre-specifying these elements in a protocol and, ideally, making them public improves credibility.

Lessons from Rare Disease Applications

In recent years, several submissions in rare diseases have relied on ECAs to support accelerated approval or reimbursement. Some succeeded, often when TTE principles were followed. Others failed, sometimes due to vague comparator definitions, outdated data, or overreliance on surrogate endpoints not accepted by HTA bodies. 

A case in point: In a rare oncology indication, a sponsor used a large academic registry to emulate the control arm of a Phase II trial. The submission was strengthened by early joint scientific advice and clear documentation of alignment between registry and trial populations. In contrast, another submission using historical chart review data failed to convince HTAs due to lack of clinical comparability and missing baseline variables.

Closing Thought

External control arms can unlock access and speed in rare disease development. But they must be built on more than convenience. TTE helps ensure these comparisons are not just methodologically rigorous but also decision-relevant. As regulators and HTA bodies become more discerning, the question is no longer if TTE should be used in designing ECAs but how soon in the development timeline it should be embedded.