Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0636-y) contains supplementary material, which is available to authorized users.

Agreement between results of meta-analyses from case reports and clinical studies, regarding efficacy and safety of idursulfase therapy in patients with mucopolysaccharidosis type II (MPS-II). A new tool for evidence-based medicine in rare diseases

“…Some authors have underlined the utility of N-of-1 trials to compare the effect of different treatments in only one patient [34]. These designs can randomize repeated cycles of treatment challenges (e.g., A-B-A-B) in a single participant, in which A is the test drug and B is the comparison drug.…”

Exploring new uses for existing drugs: innovative mechanisms to fund independent clinical research

“…Furthermore, interviewees mentioned that advancements in research methodology and technology could lead to more innovative trial designs for drug repurposing research [ 96 – 98 ]. Various study designs have been proposed in scientific literature to replace or at least complement traditional RCTs, such as pragmatic and low-interventional trials, registry-based RCTs [ 99 , 100 ], N-of-1 trials for rare diseases [ 101 ], multi-arm/multi-stage or platform trials [ 96 – 98 ] and real-world patient data studies [ 8 , 102 ]. Yet, further research focused on clinical research methodology is needed to explore the application potential of such study designs to drug repurposing.…”

Moving somatic gene editing to the clinic: routes to market access and reimbursement in Europe

“… Route Example Main authority Initiator(s) Level of approval Funding Main requirement Benefit Disadvantage ATMP Yescarta/ Luxturna [ 13 ] EMA Pharmaceutical company European National decisions after market access The product should be defined as an ATMP and safety evaluated in a dossier Systematic large-scale evaluation of safety and efficacy of the specific product, often with requirements after approval Lengthy and labor-intensive, impacting pricing of drugs Compassionate use No SGTs registered EMA advises national authorities Physician attunes with the pharmaceutical company National Pharmaceutical company Unmet medical need and clinical research or market approval procedures are ongoing Access before market approval for (small) groups of patients with a serious unmet medical need Temporary arrangement. The decreased incentive for commercial companies to invest in drugs for small groups of patients (no income during CU-phase) and selection of patients in a phase where limited stock is available is challenging (leading to international differences, or even lotteries) [ 18 ] Named patients Ephedrine for myasthenia gravis (not SGT) [ 29 ] Dutch Health and Youth Care Inspectorate [ 19 ] Doctors declaration required. Access granted through exemption at the individual level (permission for one patient) National reimbursement at the discretion of health insurance company [ 19 ] The unmet medical need for an individual patient and availability of the product in another country, possibly for another indication [ 19 ] Tailored access for the patient with unmet medical needs to treatments for very rare conditions Permission is only granted on a case-to-case basis for one patient (labor-intensive/not suitable for large groups), differences in national regulations, not necessarily reimbursed (in the Netherlands).…”