Designing clinical trials for rare diseases requires balancing scientific rigour with practical realities.

A key challenge – the frequent use of a 2:1 randomisation ratio.

Why is this necessary? This is necessary for ethical reasons, to support patient recruitment, and to help collect robust safety data, amongst other reasons.

➡️ Ethics & Appeal: Patients facing life-changing conditions want more than a 50/50 chance at a potential therapy. A 2:1 ratio boosts trial appeal, which is critical for recruitment in ultra-rare populations.

➡️ Safety: A 2:1 ratio accelerates the collection of vital safety and tolerability data on novel treatments, de-risking development for all stakeholders.

2:1 randomisation comes at a cost: loss of statistical power and the ability to demonstrate statistical significance, especially with a binary endpoint. The smaller control group can make it challenging to present definitive comparative evidence.

Deal-breaker? Absolutely not.

The “power problem” isn’t a dead end—it’s a design challenge that can be overcome.

This is where the strategic use of external data becomes critical. Leveraging well-curated historical control data or real-world evidence can provide a stronger foundational context for the observed treatment effect, helping to interpret the results.

By combining a thoughtful trial design (like adaptive protocols or sensitive endpoints) with a strong supporting narrative that incorporates all the available evidence, we can confidently use 2:1 randomisation.

It allows us to do the right thing for patients and build a credible case for regulatory approval without compromising on access and commercial success.