Toward responsible clinical n-of-1 strategies for rare diseases

Victoria M Defelippe; Ghislaine J M W van Thiel; Willem M Otte; Roger E G Schutgens; Bas Stunnenberg; Helen J Cross; Finbar O'Callaghan; Valentina De Giorgis; Floor E Jansen; Emilio Perucca; Eva H Brilstra; Kees P J Braun

doi:10.1016/j.drudis.2023.103688

Toward responsible clinical n-of-1 strategies for rare diseases

Drug Discov Today. 2023 Oct;28(10):103688. doi: 10.1016/j.drudis.2023.103688. Epub 2023 Jun 24.

Affiliations

¹ Department of Child Neurology, UMCU Brain Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France. Electronic address: v.m.defelippe-2@umcutrecht.nl.
² Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
³ Department of Child Neurology, UMCU Brain Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
⁴ Van Creveldkliniek, Benign Hematology Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; European Reference Network for Oncological and non-oncological Rare Hematological Diseases (EuroBloodNet), Hôpital St Louis / Université Paris 7, 1 Avenue Claude Vellefaux, 75475 Paris, France.
⁵ Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Center for Medical Neuroscience, Radboud University Medical Center, Thomas van Aquinostraat 4, 6525 GD Nijmegen, the Netherlands.
⁶ European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France; University College London (UCL) Great Ormond Street, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
⁷ European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France; Paediatric Neuroscience, UCL Great Ormond Street, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
⁸ European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France; Fondazione Mondino National Institute of Neurology, University of Pavia, Via Mondino 2, 27100 Pavia, Italy.
⁹ Department of Child Neurology, UMCU Brain Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France.
¹⁰ European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France; Department of Medicine, University of Melbourne (Austin Health), Heidelberg, VIC 3084, Australia; Department of Neuroscience, Monash University, Melbourne, VIC, Australia.
¹¹ European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France; Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
¹² European Reference Network for Rare and Complex Epilepsies (EpiCare), Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, c/o Pr Arzimanoglou, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677 Bron, France; Department of Child Neurology, UMCU Brain Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.

PMID: 37356616
DOI: 10.1016/j.drudis.2023.103688

Abstract

N-of-1 strategies can provide high-quality evidence of treatment efficacy at the individual level and optimize evidence-based selection of off-label treatments for patients with rare diseases. Given their design characteristics, n-of-1 strategies are considered to lay at the intersection between medical research and clinical care. Therefore, whether n-of-1 strategies should be governed by research or care regulations remains a debated issue. Here, we delineate differences between medical research and optimized clinical care, and distinguish the regulations which apply to either. We also set standards for responsible optimized clinical n-of-1 strategies with (off-label) treatments for rare diseases. Implementing clinical n-of-1 strategies as defined here could aid in optimized treatment selection for such diseases.

Keywords: clinical care; learning healthcare systems; methodology; personalized medicine; rare diseases; single patient trial.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Patient Selection
Rare Diseases* / drug therapy
Treatment Outcome