Assessment of frequency and reporting of design changes among clinical drug trials published in influential medical journals

  • Daniel Shepshelovich
    Medicine A, Rabin Medical Center, Beilinson Hospital, Jabotinsky 39, Petah Tikva 4941492, Israel

    Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Tel Aviv 6997801, Israel
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  • Dafna Yahav
    Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Tel Aviv 6997801, Israel

    Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Jabotinsky 39, Petah Tikva 4941492, Israel
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  • Ariadna Tibau
    Oncology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Carrer se Dant Quinti 89, Barcelona 08041, Spain
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  • Eitan Amir
    Corresponding author.
    Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre, The University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada
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Published:August 19, 2019DOI:


      • Modifications of trial design after initiation can undermine scientific validity.
      • Design changes were identified in most drug trials published in influential journals.
      • Most modifications were not reported in the related publications.
      • Justification for such modifications should be reported more clearly.



      Modifications of primary outcome measures after trial initiation can undermine their scientific validity. We aimed to quantify these changes and to characterize potential predictors in clinical drug trials published in high impact factor general medicine journals.


      The study cohort included all prospective, adult drug clinical trials published in the New England Journal of Medicine, JAMA and Lancet between June 2017 and May 2018. The matching entries effective at trial initiation were compared with those effective on July 2018, thereby identifying amendments to primary outcome definitions and assessment timeframes and the planned sample size (defined as >10% change). The primary publications were reviewed for reporting of these amendments. Associations between identified changes and trial characteristics were explored using logistic regression.


      Of the 147 included trials, modifications to primary outcome measures were identified in 80 (54%). Primary outcome definitions, outcome assessment timeframes and the planned sample size were modified in 28 (19%), 12 (8%) and 65 (45%) of registry entries, respectively; of which 21 (75%), 11 (92%), and 33 (51%), respectively, were not reported in the related publications. There were no significant associations between modifications in registry entries and study characteristics.


      Approximately half of trials published in influential medical journals present changes to the design while patient accrual is ongoing, and two thirds of them are unreported. Justification for such modifications should be reported more clearly. Reviewers, editors and readers should consult for a more comprehensive report of the evolution of key study methods.


      CI (confidence intervals), HR (hazard ratio), IQR (interquartile range), FDA (Food and Drug Administration), OR (odds ratios), RCT (randomized controlled trial)
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      Linked Article

      • Clinical trial publications: A sufficient basis for healthcare decisions?
        European Journal of Internal MedicineVol. 71
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          Clinical studies remain the single most important information source of the scientific basis on which healthcare decisions are taken. This applies to population-level decisions taken by drug regulators or healthcare payers as well as individual-level decisions taken by patients and their physicians. With respect to drug treatments, adequately designed, executed, and reported randomised controlled trials (RCTs) have often been described as the “gold standard” for decision making. High expectations and ethical responsibilities are riding on publications of RCTs in peer reviewed journals.
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