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Analysis and reporting of adverse events in randomised controlled trials: a review
Rachel Phillips1, Lorna Hazell2,3, Odile Sauzet4
1Faculty of Medicine, School of Public Health, Imperial College London, London, UK.
Insights
This study reveals inconsistent collection and reporting of adverse event (AE) data in clinical trials, underutilizing randomized controlled trials (RCTs) for safety insights. Improvements in AE data analysis and standardized reporting are crucial for accurate safety synthesis.
Area of Science:
- Clinical Trials Methodology
- Pharmacovigilance
- Biostatistics
Background:
- Adverse events (AEs) are critical safety indicators in drug development.
- Randomized controlled trials (RCTs) are a primary source of efficacy data but also offer valuable safety information.
- Current practices for collecting, reporting, and analyzing AE data in RCTs require examination.
Purpose of the Study:
- To evaluate contemporary methods for collecting, reporting, and analyzing adverse events (AEs) in randomized controlled trials (RCTs).
- To identify inconsistencies and areas for improvement in AE data handling within high-impact medical journals.
Main Methods:
- A systematic review of 184 RCT reports published in four high-impact medical journals (BMJ, JAMA, Lancet, NEJM) between September 2015 and September 2016.
- Data extraction using a piloted checklist focused on AE collection, severity assessment, causality, reporting criteria, and analysis methods.
- Independent verification of a subset of extracted data to ensure quality.
Main Results:
- Only 62% of studies reported spontaneous AE collection, with just 29% detailing specific prompts used.
- While 80% reported patient withdrawals, only 35% specified if AEs caused these withdrawals.
- Most studies (84%) ignored repeated AEs, and 47% performed underpowered hypothesis tests for binary outcomes.
Conclusions:
- Adverse event data collection, reporting, and analysis in RCTs are inconsistent and underutilized for safety assessment.
- Key areas for improvement include reducing data loss in patient-level analysis and avoiding inappropriate hypothesis testing.
- Standardized reporting practices and guidance for AE causality assessment are needed to enhance safety data synthesis and statistical methodology.
Objective:
To ascertain contemporary approaches to the collection, reporting and analysis of adverse events (AEs) in randomised controlled trials (RCTs) with a primary efficacy outcome.
Design:
A review of clinical trials of drug interventions from four high impact medical journals.
Data Sources:
Electronic contents table of the BMJ, the Journal of the American Medical Association (JAMA), the Lancet and the New England Journal of Medicine (NEJM) were searched for reports of original RCTs published between September 2015 and September 2016.
Methods:
A prepiloted checklist was used and single data extraction was performed by three reviewers with independent check of a randomly sampled subset to verify quality. We extracted data on collection methods, assessment of severity and causality, reporting criteria, analysis methods and presentation of AE data.
Results:
We identified 184 eligible reports (BMJ n=3; JAMA n=38, Lancet n=62 and NEJM n=81). Sixty-two per cent reported some form of spontaneous AE collection but only 29% included details of specific prompts used to ascertain AE data. Numbers that withdrew from the trial were well reported (80%), however only 35% of these reported whether withdrawals were due to AEs. Results presented and analysis performed was predominantly on 'patients with at least one event' with 84% of studies ignoring repeated events. Despite a lack of power to undertake formal hypothesis testing, 47% performed such tests for binary outcomes.
Conclusions:
This review highlighted that the collection, reporting and analysis of AE data in clinical trials is inconsistent and RCTs as a source of safety data are underused. Areas to improve include reducing information loss when analysing at patient level and inappropriate practice of underpowered multiple hypothesis testing. Implementation of standard reporting practices could enable a more accurate synthesis of safety data and development of guidance for statistical methodology to assess causality of AEs could facilitate better statistical practice.
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