Abstract
BackgroundInexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results.ResultsThe trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug.ConclusionsIn theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.
Highlights
Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications
In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions
In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups
Summary
Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Current treatment paradigms for rare diseases include expensive, novel orphan drugs and cheaper medicines with a longer history of use. The latter are often prescribed off-label for rare indications, whereas they may be licensed for other, more common indications. The paragraph details specifics of the Dutch health care system which hinder the reimbursement of moderately priced, older medicines for rare diseases It is explained how this research contributes to a roadmap which can be used in other countries as well, suggesting opportunities for “rediscovery” of cheap old drugs for rare disease indications. To help generalize from the situation in the Netherlands, key concepts are shown in italics
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