Rethinking Natural History Data in Rare Neurological Disease Trials

In rare neurological disease development, progress can be limited not by scientific ambition, but by the data needed to support it. For many programs—particularly in pediatric and neurodegenerative conditions—high-quality natural history data underpins trial design, regulatory confidence and long-term development decisions. Yet building datasets that are both scientifically robust and feasible for patients and families remains a significant challenge.

In a recent episode of Cortex Conversations, Fortrea leaders Louise Kearney, Head of Rare Disease, Pediatrics and Cell & Gene Therapy Strategy and Delivery,  and Hannah Simonds, Director of Patient Recruitment and Engagement joined Karmen Truzpek Senior Director of Scientific Programs from Global Genes to explore how clinical development teams can rethink natural history studies to better reflect real-world patient experience—while still meeting regulatory expectations.

Why traditional natural history studies fall short in rare disease trials

Many rare disease natural history studies originate at single academic sites. While these efforts are often well intentioned, they inherently narrow participation. Restrictive eligibility criteria, travel burden, longer clinic visits and demanding assessment schedules can exclude families who are unable to attend—or whose children fall outside a narrow “middle band” of disease severity.

This creates gaps in representativeness and raises important questions when natural history data is later considered for use as an external control. If datasets do not capture the full spectrum of disease progression, their value in regulatory decision making may be limited.

Designing patient-centric early phase rare neurological disease trials

Families living with rare neurological conditions often want to contribute to research—but feasibility and early engagement matters. Disease severity, fatigue, behavioral challenges and daily routines all influence what is realistic to ask of participants – especially pediatric patients and their families.

Co-developing study designs with patient communities early on helps teams understand what data can be collected reliably, how visits should be structured and which assessments create unnecessary burden. Importantly, what works for one condition—or one age group—may not translate to another.

“These natural history studies are generally in small, geographically dispersed communities, participants are often asked to travel far and give a great deal. If we don’t codesign studies with these communities — aligning outcomes with what truly matters and using tools like remote assessments, wearables and video capture to reduce burden — we risk generating trials that are elegant, but not workable. Meaningful science has to be doable science.”

— Louise Kearney, Head of Rare Disease, Pediatrics and Cell & Gene Therapy Strategy and Delivery

The evolving role of remote and hybrid clinical data collection approaches

Remote and hybrid data collection methods are gaining momentum, particularly in areas such as mobility, seizure activity and sleep. Wearables, video-based assessments and at home monitoring offer opportunities to capture data that reflects daily life rather than episodic clinic snapshots.

Regulators have shown an openness to these approaches, but with clear expectations: remote data must be evaluated alongside established clinical measures. As a result, many programs are running side-by-side comparisons to demonstrate data quality and relevance before broader adoption.

When implemented thoughtfully, these approaches can help reduce patient burden, support longitudinal follow-up and improve retention—an ongoing challenge in long running natural history studies.

Key Takeaways for Neuroscience Development Teams Designing Natural History Studies

For neuroscience clinical teams, the message is clear: natural history studies can require the same level of rigor, planning and operational discipline as interventional trials, especially if being used as future control group data. Protocol design decisions made early—around endpoints, visit structure and data collection methods—have lasting consequences for feasibility and downstream regulatory use.

Natural history data is not just an academic asset; it represents the lived experience of patients and families. Designing studies that respect that reality can lead to better data, stronger development programs and clearer regulatory pathways.

To explore these insights in more depth, listen to the full podcast episode ofCortex Conversationsand hear directly from those working at the intersection of neuroscience, operations and patient experience.

Or, if you’re ready to talk to us about yourneuroscienceclinical research, and how we can help –get in touch here