Extension Reports in Clinical Trials: A Systematic Review and Consequent Guidance.

BACKGROUND: Following the primary publication of a clinical trial, questions of longer-term efficacy and safety remain unanswered. Investigators often have sequel publications based on extended follow-up; yet, no guidelines exist for such extension reports. OBJECTIVES: The purpose of this analysis was to assess the characteristics of extension reports of cardiovascular trials published in 7 high-impact medical journals METHODS: We searched MEDLINE to identify cardiovascular trial extension papers published between January 2019 and October 2023 in 7 high-impact medical journals. Extension reports were defined as those presenting additional follow-up data after publication of the primary results. Papers were screened by 2 reviewers before extracting data using a standard proforma. RESULTS: After screening 1,388 papers, 69 extension reports across 64 trials were identified. A variety of cardiovascular topics were covered, coronary heart disease (n = 20) being the most common. Interventions were medical devices, drugs, surgery, or treatment strategies. Duration of follow-up varied considerably, most common being an original 1-year report (n = 20) with extension at 2, 3, 5, or 10 years. Nearly all extension reports had a superiority hypothesis (n = 68). Most extensions (n = 53) examined the same primary outcome as the original publication. There were also 7 nonrandomized open-label extensions, which suffered from the lack of a concurrent control arm. In 18 reports, treatment crossovers were permitted during the extension, and in 16 cases, alternatives to analysis by intention to treat were utilized. One-half of the extension studies were prespecified (n = 38), and only 10 had dedicated protocols or statistical analysis plans. No study used multiplicity corrections to control type I error across the totality of evidence. Landmark analyses were common (n = 39) which, while descriptively useful, were not based on the original randomized groups. Considerable loss to follow-up (>10%) occurred in 10 of 50 extension reports with clear reporting of this issue. For some trials, the conclusions regarding treatment effects were altered by the extended follow-up. In a previous survey of cardiovascular trials published in the New England Journal of Medicine, Lancet, and Journal of the American Medical Association in 2019, we identified a total of 23 of 84 trials involving extensions in some form. CONCLUSIONS: This first systematic investigation into the reporting of extension studies found a great diversity in practice, noting several issues that need more adequate consideration. Considerations are provided on what trialists should consider when planning, conducting, and reporting extension studies.

Duke Scholars

Author Frank Wesley Rockhold Biostatistics & Bioinformatics, Division of Biostatistics