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  • Best practices in phase III clinical trials on DMTs for multiple sclerosis: a systematic analysis and appraisal of published trials

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Multiple sclerosis
Systematic review
Best practices in phase III clinical trials on DMTs for multiple sclerosis: a systematic analysis and appraisal of published trials
  1. Marta Mascarenas-Garcia1,2,
  2. Alejandro Rivero-de-Aguilar1,3,
  3. Mónica Pérez-Ríos1,4,5,
  4. Alberto Ruano-Raviña1,4,5,
  5. Miguel Angel Llaneza-Gonzalez6,
  6. Cristina Candal-Pedreira1,4,
  7. Julia Rey-Brandariz1,
  8. Leonor Varela-Lema1,4,5
  1. 1 Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela, Spain
  2. 2 Preventive Medicine and Public Health, University Hospital Complex of Santiago de Compostela, Santiago de Compostela, Spain
  3. 3 Department of Neurology, University Hospital Complex of Pontevedra, Pontevedra, Spain
  4. 4 Health Research Institute of Santiago de Compostela (Instituto de Investigación Sanitaria de Santiago de Compostela - IDIS), Santiago de Compostela, Spain
  5. 5 Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública/CIBERESP), Madrid, Spain
  6. 6 Department of Neurology, Central University Hospital of Asturias, Oviedo, Spain
  1. Correspondence to Alejandro Rivero-de-Aguilar, Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain; alejandro.riverodeaguilar{at}gmail.com

Abstract

Background Great advances have been made in the field of multiple sclerosis (MS) therapy due to the publication of numerous randomised clinical trials (RCTs). In this study, we carried out a critical appraisal of phase III RCTs of disease-modifying therapies (DMTs) for MS published after 2010, intending to identify critical areas of improvement.

Methods We performed a systematic search of published RCTs on MS from January 2010 until December 2021. RCTs were assessed using an ad-hoc tool. This tool was developed based on existing generic methodological instruments and MS-specific guidelines and methodological papers. It included 14 items grouped in 5 domains: methodological quality, adequacy and measurement of outcomes, adverse event reporting, applicability and relevance of results, and transparency and conflict of interest.

Results We identified 31 phase III RCTs. Most of them were fully compliant in terms of sample size (87%), randomisation (68%), blinding (61%), participant selection (68%), adverse event reporting (84%) and clinical relevance (52%). Only a few were compliant in terms of participant description (6%), comparison (42%), attrition bias (26%), adequacy of outcome measures (26%), applicability (23%), transparency (36%) and conflict of interest (6%). None were compliant in terms of analysis and reporting of outcomes. The most common limitations related to the absence of comorbidity data, unjustified use of placebo, inadequacy of outcomes design and absence of protocol and/or prospective registration.

Conclusions RCTs for DMTs in MS have relevant and frequent limitations. These should be addressed to enhance their quality, transparency and external validity.

Data availability statement

Data are available upon reasonable request. This publication is part of the PhD work of the first author. Full data are available upon reasonable request (contact: Alejandro Rivero-de-Aguilar, alejandro.riverodeaguilar@gmail.com).

https://doi.org/10.1136/jnnp-2023-331733

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    Data availability statement

    Data are available upon reasonable request. This publication is part of the PhD work of the first author. Full data are available upon reasonable request (contact: Alejandro Rivero-de-Aguilar, alejandro.riverodeaguilar@gmail.com).

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    Footnotes

    • Twitter @MartaMascarenas

    • Contributors MM-G: data extraction, methodology, statistical analysis, interpretation of results, writing of the manuscript draft. AR-d-A: study conceptualisation, data extraction, methodology, interpretation of results, revision and edition of the manuscript. MP-R: study conceptualisation, revision and edition of the manuscript. AR-R: study conceptualisation, revision and edition of the manuscript. MAL-G: interpretation of results, revision and edition of the manuscript. CC-P: interpretation of results, revision and edition of the manuscript. JR-B: interpretation of results, revision and edition of the manuscript. LV-L: study conceptualisation, methodology, statistical analysis, interpretation of results, revision and edition of the manuscript, supervision of the manuscript. MM-G is responsible for the overall content as guarantor.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.