Silent protocol modifications in multiple sclerosis clinical trials: a registry-based cross-sectional study.

Abstract

Background: Changes in the original protocol of clinical trials should be clearly declared to the readers of journal publications. Otherwise, they can lead to selective outcome reporting bias or distort the appropriate judgement of the study's external validity and statistical power, among other problems.

Objectives: To identify silent protocol modifications in phase III and IV clinical trials examining multiple sclerosis (MS) drugs that have been carried out between 2010 and mid-2023.

Design: Comparative analysis of ClinicalTrials.gov and associated peer-reviewed journal publications.

Methods: An advanced search in ClinicalTrials.gov was performed and consecutive searches in PubMed, EMBASE and Google Scholar were conducted looking for the main journal publication derived from each trial. Information regarding trial design, eligibility criteria, primary outcomes and sample size estimation was simultaneously collected from ClinicalTrials.gov and publications, and subsequently compared.

Results: In total, 112 trials were appraised. Most studies matched between data sources in terms of study arms (96.4%), assignment (99.1%) and randomization (100.0%). Concordance was also high but comparatively lower for masking (82.1%). A total of 3051 eligibility criteria were extracted, 45.5% of which matched, 25.1% were omitted in publications, 2.8% were modified and 26.6% were added. Fifty-eight trials (51.8%) completely matched regarding their published primary outcomes, whereas 20 had major inconsistencies (17.9%) and 34 (30.4%) minor inconsistencies. Fourteen trials were inconsistent in their estimated sample size; among these, the median difference between registry and publications was 36.5 individuals (interquartile range 17-161). The proportion of trials exhibiting silent protocol changes was similar regardless of study phase, industry involvement or type of registration.

Conclusion: Silent protocol changes are common in MS clinical trials and potentially hinder the interpretation and applicability of results. Efforts must be made to promote more transparency in the field of MS clinical research.