26 November 2025

Utrecht, 14th November 2025 – The Thematic Working Group on Clinical Outcomes in Early-Phase Trials of the European College of Neuropsychopharmacology (ECNP) has published a
important letter to the editor in the Orphanet Journal of Rare Diseases, highlighting the urgent need to reform clinical trial methodologies for rare neuropediatric diseases.

Led by Dr María T. Acosta and Dr Silvia Zaragoza Domingo, the publication synthesizes the
insights of international experts, including clinicians, researchers, regulators, industry leaders, and patient advocates, who participated in dedicated working sessions throughout 2023. Their conclusion is clear: current approaches are failing the children who need them most.

“Clinical trials in rare neuropediatric diseases require flexible, collaborative, and patient-centered approaches, as well as the use of available but underutilized methodologies,” said Dr. Zaragoza Domingo. “This work is a firm step towards building more effective and humane models that address the real needs of families and help accelerate the development of transformative therapies.”

A Call to Action

The letter identifies critical methodological gaps that hinder progress, including:
• Inadequate outcome measures that fail to reflect meaningful change.
• Lack of tailored tools for small, heterogeneous patient populations.
• Disconnect between biological markers and clinical manifestations.
• Limited use of digital health tools and real-world data.
• Insufficient involvement of caregivers in outcome reporting.

These limitations have real-world consequences: promising therapies may be rejected due to outdated metrics, delaying access to life-changing treatments for children with severe disabilities, frequent seizures, and shortened life expectancy.

Towards Solutions

The ECNP group proposes a shift in mindset across all stakeholders. Among the solutions
discussed are:
• Development of collaborative platforms to create and validate new outcome
instruments.
• Use of natural history data and AI-driven tools to personalise assessments.
• Integration of caregiver-reported outcomes and ecological momentary evaluations.
• Encouragement from regulators and funders to pilot innovative methodologies.

Key Messages

Thematic Working Group on Clinical Outcomes in Early-Phase Clinical Trials, European College of  Neuropsychopharmacology (ECNP)
• Children with rare neurological diseases deserve trials that reflect their reality, not outdated metrics.
• Innovation in therapies must be matched by innovation in how we measure benefit.
• Families and patients are ready for change. Regulators must catch up.

This publication marks the beginning of a broader initiative. A follow-up scientific paper focused on solutions is currently in preparation. The authors hope this letter will spark dialogue and action among regulators, funders, and clinical researchers worldwide.
The full article is available in the October 2025 issue of the Orphanet Journal of Rare Diseases, and can be accessed online here.

About the Working Group on Clinical Outcomes in Early-Phase Clinical Trials

The ECNP thematic working group Clinical Outcomes in Early-Phase Clinical Trials brings together experts from over 15 countries with the aim of improving the effectiveness of early-phase clinical trials in central nervous system diseases. The group promotes the validation of patient-centered clinical assessment tools and the development of innovative methodologies.
Through its work, it also fosters collaboration among researchers, industry, patient organisations, and regulatory bodies to accelerate the development of new therapies.
This press release is distributed by the ECNP on behalf of the ECNP working group on clinical outcomes in early-phase trials. The press release was developed by the working group, with
the assistance of the Dravet Syndrome Foundation Spain.

More information and interviews:
ECNP Press Officer, Tom Parkhill: press@ecnp.eu tel +00 39 349 238 8191
Simona Giorgi, Dravet Syndrome Foundation Spain comunicacion@dravetfoundation.eu +34 622 88 35 58

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