SEARCHNARRATIVE_REVIEWneurology, pediatrics

narrative_review·neurology, pediatrics, preclinical research, clinical trial, research methods·PMC10032345

Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration

Frontiers in Neurology · 8 authors, 9 centres

AI SUMMARY

FIDELITY 100%

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

The authors outline how reliance on symptom-based endpoints in advanced disease limits the potential for disease-modifying therapies, since neuronal loss in the brain is irreversible.

Full summary

552 CHARS

The authors outline how reliance on symptom-based endpoints in advanced disease limits the potential for disease-modifying therapies, since neuronal loss in the brain is irreversible. They advocate for a paradigm shift toward pre-symptomatic treatment guided by Primary Disease Activity Biomarkers and surrogate endpoints rather than clinical symptoms. The review discusses specific trial design strategies including the use of natural history data, within-patient change analyses, and regulatory flexibility consistent with the 21st Century Cures Act.

STUDY TYPE

narrative_review

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10032345

Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration

Frontiers in Neurology

READ THE FULL PAPER

ABSTRACT

Abstract Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations. Keywords: ultra-rare disease, orphan disease, clinical trial design, inborn errors of metabolism, movement disorders

CITATION EXPORT

Aleksandar Videnovic, Helle C V Pfeiffer, Anna Tylki-Szymańska et al.. Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration. Frontiers in Neurology. (2023). https://doi.org/10.3389/fneur.2023.1098454

AUTHORS

8 · 9 CENTRES

Aleksandar Videnovic, Helle C V Pfeiffer, Anna Tylki-Szymańska, Elizabeth Berry-Kravis, Fatih Ezgü, Jitendra Ganju, Agnieszka Jurecka, Anthony E Lang

1Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
2Department of Child Neurology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
3Department of Pediatrics, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
4Department of Pediatrics, Nutrition and Metabolic Diseases, Children's Memorial Health Institute IPCZD, Warsaw, Poland
5Department of Pediatrics, Neurological Sciences, Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
6Department of Pediatrics, Gazi University Faculty of Medicine, Ankara, Türkiye
7Consultant to BridgeBio, San Francisco, CA, United States
8CoA Therapeutics, Inc., A BridgeBio Company, San Francisco, CA, United States
9Department of Medicine (Neurology), Edmond J. Safra Program in Parkinson's Disease, and the Rossy Progressive Supranuclear Palsy Centre, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada