ZonMW (the Netherlands organisation for health research and development) has awarded two research grants for n-of-one trial related projects.
Project 1: From rationing to rationality: an n-of-one trial service for off-label medicines for rare (neuromuscular) diseases
Background
In the Netherlands, expensive medicines are not reimbursed for off-label use unless there is sufficient evidence of efficacy. Patients with rare diseases are at a disadvantage because the burden of proof is difficult to meet. There are obstacles both for industry and academia to performing traditional randomized, controlled trials. Moreover, the reimbursement rules discourage doctors from prescribing expensive medicines off-label, even to small groups of patients. Thus, evidence will not even accrue from case series.
The Dutch health care insurance board is the main advisory body on financing and reimbursement of pharmaceutical care. It generally approves only ‘rational’ pharmacotherapy, defined as being effective, safe, and cost-effective. At the same time, the board has recognized the need to develop forms of conditional financing of promising, innovative healthcare.
Examples of reimbursement problems with off-label medicines are known from many rare disease areas, e.g. oncology, movement disorders, neuromuscular diseases and more. This project focuses on neuromuscular disorders, as a pilot group. The tool to be developed will, if successful, serve many other groups of patients with serious, chronic, rare disease.
Goals
This project will start the development of an ‘n of 1’ trial service, integrated in the Dutch health care (assessment) system. The aim is to promote equitable pharmaceutical care for patients with rare diseases and to generate evidence on the efficacy of promising, off-label drugs. The ‘product’ of the trial service will eventually be well-documented case series, from situations where small numbers of patients have used promising drugs, under controlled conditions, in n of 1 trials. This is a developmental project. It will set the stage for a follow-up project, in which n of 1 trials will be actually be carried out.
Strategy
Neurologists have already produced a list of candidate neuromuscular indications, where off-label reimbursement is a problem. This list will be enriched with problems reported by members of a neuromuscular patients’ organization. Candidate neuromuscular conditions and promising off-label medicines will be prioritized for suitability for n of 1 trials. There is literature on how to prioritize.
Two systematic literature searches will be done. The first will survey the methodology of n of 1 trials, while the second will produce an inventory of evidence for the efficacy of specific off-label medicines for neuromuscular indications, as selected in the prioritization described above.
An invitational work conference will be organized with experts from the following fields: health law, epidemiology and biostatistics, health technology assessment, health insurance companies, pharmaceutical science, pharmaceutical industry, and ethics. Its purpose is to (1) define the preconditions necessary for formalizing and sustaining an n of 1 trial service and (2) formulate specific recommendations for pilot implementation of the n of 1 trial service, to be used in a follow-up project.
An electronic data registry system for n of 1 trials will be designed. Protocols will be written for some specific n of 1 trials for off-label neuromuscular indications. A proposal will be written for a follow-up project, in which the n of 1 trials can be performed. Follow-up studies will be considered for economic evaluation and for studying the attitudes of doctors and patients participating in the n of 1 trials.
Collaboration institutes
Vereniging Spierziekten Nederland; College voor Zorgverzekeringen; Dutch Cochrane Centre; Stichting Eerlijke Geneesmiddelenvoorziening; Prinses Beatrix Fonds; Erasmus MC, Institute for Medical Technology Assessment; VUmc, Department of Epidemiology and Biostatistics; LUMC, Department of Neurology; VUmc; EMGO+ Institute for Health and Care Research/Clinical Genetics: Section of Community Genetics (project leader: Stephanie Weinreich, s.weinreich@vumc.nl)
Project 2: Building an evidence base for efficacy of drugs for rare diseases: Bayesian hierarchical models for N-of-1 trials with informative priors.
Despite breakthroughs on molecular genetics and pathophysiology, direct benefits for patients, i.e. better and more effective treatment, lag behind, especially in rare diseases. Clearly, the established methodologies for randomized controlled clinical trials cannot be applied in rare diseases and innovative trial design is essential. Single patient trials (N-of-1) provide a systematic manner to find the best therapy for an individual patient. Aggregation of a number of N-of-1 trials using a Bayesian approach is useful to estimate treatment effectiveness for a group of patients. However, the possibilities and advantages of the Bayesian approach are not fully explored yet. Our proposal examines the use of informative priors in the hierarchical Bayesian model. Herewith, we aim to build a robust evidence base for (off-label) drugs in rare diseases, so that coverage decisions can be made. Drug efficacy (Mexiletine) will be tested on non-dystrophic myotonia patients, a group of rare muscle diseases.
Applicants: Dr. Gea Drost, neuroloog, Prof. Dr. Gert-Jan van der Wilt
