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Open Access

From rationing to rationality: an n-of-one trial service for off-label medicines for rare (neuromuscular) diseases

  • Stephanie S Weinreich1, 2Email author,
  • Charlotte Vrinten2,
  • Jan JGM Verschuuren3, 4,
  • Carin A Uyl-de Groot5,
  • Marja R Kuijpers6,
  • Ellen Sterrenburg4, 7,
  • Rob JPM Scholten8,
  • Cees FRM van Bezooijen9,
  • Marcel FTH Timmen1,
  • Sonja van Weely10 and
  • Martina C Cornel2
Orphanet Journal of Rare Diseases20127(Suppl 2):A29

Published: 22 November 2012


Rare DiseaseSystematic Literature ReviewNeuromuscular DiseaseMarketing AuthorisationScientific Support

Background and aims

In the Netherlands, off-label prescription of medicines is tolerated as a suboptimal but inevitable practice. However, patients with rare diseases are disadvantaged in claiming reimbursement for off-label or off-license drugs (here summarised as ‘off-label’). It is difficult to meet the burden of evidence-based proof on efficacy of such medicines. Consensus-based guidelines, a second-best but accepted form of evidence, are also often lacking. Both industry and academia are challenged to perform classical randomized, controlled trials for rare diseases. Moreover, reimbursement rules discourage doctors from prescribing medicines off-label, even to small groups of patients. Thus there is an impasse to creating evidence. Conditionally reimbursed, controlled n-of-one (single-patient) trials with internal randomisation (e.g. AB-BA-BA) could generate evidence on efficacy for rare, chronic conditions where the aim of treatment is symptom control. Practical and scientific support might be provided by a dedicated trial service.

This project aims to initiate development of an n-of-one trial service, embedded in the Dutch health care system, for research on efficacy and safety of certain medicines with no marketing authorisation for the rare diseases for which they are prescribed.

Methods and preliminary results

Reimbursement problems with off-label medicines were inventoried among neuromuscular specialists and patients with neuromuscular disease. This list was prioritized for medicines and indications suitable for n=1-trials. Two cases were selected for systematic literature review and development of clinical protocols for n-of-one trials. A multidisciplinary expert meeting defined the legal, ethical and scientific preconditions for starting an n-of-one trial service. Recommendations were made for performing n-of-one research in a scientifically sound and socially robust manner.

Regulatory authorities and insurers may accept evidence from n-of-one trials, provided that data can be aggregated and that benefit/risk ratio is considered. An n-of-one trial service may be justified, if it can support a broad range of rare diseases.

Authors’ Affiliations

Dutch Association for Neuromuscular Disorders, Baarn, Amsterdam, The Netherlands
VU University Medical Center, Amsterdam, The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
Dutch Neuromuscular Research Centre, The Hague, The Netherlands
Erasmus University, Rotterdam, The Netherlands
Health Care Insurance Board, Diemen, The Netherlands
Princes Beatrix Fonds, The Hague, The Netherlands
Dutch Cochrane Centre, Amsterdam, Amsterdam
Foundation for Equitable Provision of Medicines, Rotterdam, The Netherlands
former Dutch Steering Committee on Orphan Drugs, The Hague, The Netherlands


  1. Vrinten C: Part of this research was previously reported as an abstract. Mol Syndromol. 2011, 2: 274-[abstract C002-2012]Google Scholar


© Weinreich et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.