Rare Neurological Disease Trials: Smarter Design With Natural History, External Controls, And Real-World Evidence

By Dr. Syed Owais Wasti, MD, MPH, Senior Medical Director, Internal Medicine & Neuroscience

Clinical trials for rare neurological diseases are among the most challenging in the biopharmaceutical landscape. The small and often heterogeneous patient populations, combined with the progressive and variable nature of these conditions, make traditional randomized controlled trials (RCTs) difficult — if not impossible — to execute. Ethical concerns over placebo use, statistical limitations due to sample size, and operational barriers such as site recruitment and retention further compound these challenges.

To address these constraints, sponsors are increasingly turning to natural history studies and external control arms as scientifically robust and regulatorily recognized alternatives. These approaches not only provide critical context for disease progression and treatment impact but also enable evidence generation when conventional RCTs are impractical. When properly designed and validated, they can deliver insights that support both clinical development and regulatory submissions.

This blog explores how sponsors can integrate these strategies early in the development lifecycle, align with evolving regulatory expectations, and leverage experienced data and research partners to ensure methodological rigor. We will discuss best practices for building high-quality real-world datasets, ensuring statistical validity, and achieving regulatory confidence in external comparators.

From feasibility assessment to regulatory alignment, the right evidence strategy can reduce development risk, strengthen the scientific foundation of submissions, and ultimately accelerate access to transformative therapies for patients with urgent unmet medical needs.