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

BACKGROUND: Inexpensive 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. Stakehol...

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Autores principales: Weinreich, Stephanie S., Vrinten, Charlotte, Kuijpers, Marja R., Lipka, Alexander F., Schimmel, Kirsten J. M., van Zwet, Erik W., Gispen-de Wied, Christine, Hekster, Yechiel A., Verschuuren, Jan J. G. M., Cornel, Martina C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427624/
https://www.ncbi.nlm.nih.gov/pubmed/28494776
http://dx.doi.org/10.1186/s13023-017-0636-y
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author Weinreich, Stephanie S.
Vrinten, Charlotte
Kuijpers, Marja R.
Lipka, Alexander F.
Schimmel, Kirsten J. M.
van Zwet, Erik W.
Gispen-de Wied, Christine
Hekster, Yechiel A.
Verschuuren, Jan J. G. M.
Cornel, Martina C.
author_facet Weinreich, Stephanie S.
Vrinten, Charlotte
Kuijpers, Marja R.
Lipka, Alexander F.
Schimmel, Kirsten J. M.
van Zwet, Erik W.
Gispen-de Wied, Christine
Hekster, Yechiel A.
Verschuuren, Jan J. G. M.
Cornel, Martina C.
author_sort Weinreich, Stephanie S.
collection PubMed
description BACKGROUND: Inexpensive 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. RESULTS: The 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. CONCLUSIONS: In 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 MATERIAL: The online version of this article (doi:10.1186/s13023-017-0636-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-54276242017-05-15 Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis Weinreich, Stephanie S. Vrinten, Charlotte Kuijpers, Marja R. Lipka, Alexander F. Schimmel, Kirsten J. M. van Zwet, Erik W. Gispen-de Wied, Christine Hekster, Yechiel A. Verschuuren, Jan J. G. M. Cornel, Martina C. Orphanet J Rare Dis Research BACKGROUND: Inexpensive 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. RESULTS: The 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. CONCLUSIONS: In 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 MATERIAL: The online version of this article (doi:10.1186/s13023-017-0636-y) contains supplementary material, which is available to authorized users. BioMed Central 2017-05-12 /pmc/articles/PMC5427624/ /pubmed/28494776 http://dx.doi.org/10.1186/s13023-017-0636-y Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Weinreich, Stephanie S.
Vrinten, Charlotte
Kuijpers, Marja R.
Lipka, Alexander F.
Schimmel, Kirsten J. M.
van Zwet, Erik W.
Gispen-de Wied, Christine
Hekster, Yechiel A.
Verschuuren, Jan J. G. M.
Cornel, Martina C.
Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis
title Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis
title_full Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis
title_fullStr Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis
title_full_unstemmed Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis
title_short Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis
title_sort aggregated n-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427624/
https://www.ncbi.nlm.nih.gov/pubmed/28494776
http://dx.doi.org/10.1186/s13023-017-0636-y
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