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

Abstract

Background: In the Netherlands, some medicines are not reimbursed for off-label use without sufficient evidence of efficacy. Patients with rare (including genetic) diseases are disadvantaged because the burden of proof is difficult to meet. There are obstacles both for industry and academia to performing large-scale randomized, controlled trials for rare diseases. Reimbursement rules also discourage doctors from prescribing medicines off-label, even to small groups of patients. Controlled n-of-one (singlepatient) trials with internal randomization (e.g. AB-BA-BA) could generate evidence on efficacy for rare, chronic conditions where the aim of treatment is symptom control. Objective: 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 authorization for the rare diseases for which they are prescribed. Methods and Preliminary Results: Reimbursement problems with offlabel medicines for rare neuromuscular diseases were inventoried among neuromuscular specialists and patients with neuromuscular disease in the Netherlands. A multidisciplinary expert meeting was organized to define legal, ethical and scientific preconditions for formalizing and sustaining an n-of-one trial service. The problem was widely acknowledged by stakeholders. Willingness was expressed to consider new forms of evidence for efficacy and safety of medicines for rare diseases and personalized therapies. Recommendations and preconditions for carrying out n-of-one research in a scientifically sound and socially robust manner were given. Implications: 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 can facilitate this process.