TY - JOUR

T1 - Study design challenges and strategies in clinical trials for rare diseases

T2 - Lessons learned from pantothenate kinase-associated neurodegeneration

AU - Videnovic, Aleksandar

AU - Pfeiffer, Helle C.V.

AU - Tylki-Szymańska, Anna

AU - Berry-Kravis, Elizabeth

AU - Ezgü, Fatih

AU - Ganju, Jitendra

AU - Jurecka, Agnieszka

AU - Lang, Anthony E.

N1 - Publisher Copyright: Copyright © 2023 Videnovic, Pfeiffer, Tylki-Szymańska, Berry-Kravis, Ezgü, Ganju, Jurecka and Lang.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - clinical trial design

KW - inborn errors of metabolism

KW - movement disorders

KW - orphan disease

KW - ultra-rare disease

U2 - 10.3389/fneur.2023.1098454

DO - 10.3389/fneur.2023.1098454

M3 - Review

C2 - 36970548

AN - SCOPUS:85150740337

VL - 14

JO - Frontiers in Neurology

JF - Frontiers in Neurology

SN - 1664-2295

M1 - 1098454

ER -