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Changes in ongoing clinical trial protocol designs behind the scenes

  • Rafael Dal-Ré
    Correspondence
    Corresponding author.
    Affiliations
    Epidemiology Unit, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Avda Reyes Católicos 2, E-28040 Madrid, Spain
    Search for articles by this author
      The implications and relevance of a study showing that 54% of clinical trials recently published in the three most influential general medicine journals New England Journal of Medicine, Lancet and JAMA presented modifications in important study design features after recruitment of the first trial participant [
      • Shepshelovich D
      • Yahav D
      • Tibau A
      • Amir E
      Assessment of frequency and reporting of design changes among clinical drug trials published in influential medical journals.
      ], have been commented in this Journal by four experts [
      • Huisman MV
      • Dekkers OM
      Clinical trial results - A closer look under the surface.
      ,
      • Eichler HG
      • Rasi G
      Clinical trial publications: A sufficient basis for healthcare decisions?.
      ]. These Commentaries were written from two different and complementary perspectives, that of clinicians/investigators [
      • Huisman MV
      • Dekkers OM
      Clinical trial results - A closer look under the surface.
      ] and that of regulators [
      • Eichler HG
      • Rasi G
      Clinical trial publications: A sufficient basis for healthcare decisions?.
      ]. These experts addressed different issues related to Shepshelovich et al [
      • Shepshelovich D
      • Yahav D
      • Tibau A
      • Amir E
      Assessment of frequency and reporting of design changes among clinical drug trials published in influential medical journals.
      ] findings, but coincided in highlighting three aspects [
      • Huisman MV
      • Dekkers OM
      Clinical trial results - A closer look under the surface.
      ,
      • Eichler HG
      • Rasi G
      Clinical trial publications: A sufficient basis for healthcare decisions?.
      ]: a) protocol modifications of primary endpoint, of endpoint timeframe assessment and of sample size once recruitment of participants has started, may undermine the validity of trial results; b) most amendments were not mentioned in articles reporting trial results; and c) how to address these two important issues. These commentators have similar views regarding the relevance of the first aspect; conversely, they have different approaches with respect to the other two. The relevance of primary endpoint modifications with regards to the trial validity lays on whether the change alters the interpretation of the results, and when the change was introduced. The importance of reporting or not the modification lays on the reasons supporting it and, as a general principle, on the expected transparency of trial reporting. Finally, how to address these issues depends, in part, on whether the trials belong or not to a development clinical plan of an experimental medicine (or new indication).

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