Analysis and reporting of adverse events in randomised controlled trials: a review

Phillips, Robert; Hazell, Lorna; Sauzet, Odile; Cornelius, Victoria

doi:10.1136/bmjopen-2018-024537

Cited by 149 publications

(156 citation statements)

References 52 publications

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“…This review agrees with other similar publications focusing on drug safety assessment in clinical trials that have noted the need for further improvement in the statistical analysis of the safety data [9,37]. This review concurs with a recent review that has noted that inappropriate handling of multiple test is prevalent, although their review focussed on four high impact journals, AE in general and a short time of review period [38]. Issues raised in this review include time-dependence of AEs, informative censoring due to discontinuation of treatment because of AEs, safety graphs, and repeated occurrence of AEs and multivariate longitudinal structure of laboratory data that yields complex correlation.…”

Section: Discussionsupporting

confidence: 88%

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Patson

Mukaka

Otwombe

et al. 2020

Malar J

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Background: Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy.Results: Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/ counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher's exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann-Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%). Conclusion:The review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data.

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Section: Discussionsupporting

confidence: 88%

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Patson

Mukaka

Otwombe

et al. 2020

Malar J

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show abstract

“…This review concurs with a recent review that has noted that inappropriate handling of multiple test is prevalent, although their review focussed on four high impact journals, AE in general and a short time of review period (39). Issues raised in this review include time-dependence of AEs, informative censoring due to discontinuation of treatment because of AEs, safety graphs, and repeated occurrence of AEs and multivariate longitudinal structure of laboratory data that yields complex correlation.…”

Section: Reported Statistical Methodssupporting

confidence: 76%

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Patson

Mukaka²,

Otwombe

et al. 2020

Preprint

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Background Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of antimalarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. We have therefore conducted a systematic review to establish the current practice in statistical analysis for antimalarial drug safety in pregnancy. Methods We searched PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials for original English articles reporting Phase III (randomized controlled trials) RCTs on antimalarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. Results Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n=18, 100%) and mean/median (n=2, 11.1%). Results presentation included tabular (n=16, 88.9%) and text description (n=2, 11.1%). Univariate inferential methods were reported in most trials (n=16, 88.9%); including Chi-square/Fisher`s exact test (n=12, 66.7%), t-test (n=2, 11.1%) and Mann-Whitney/Wilcoxon test (n=1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n=4, 22.2%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n=7, 38.9%). Conclusion The review demonstrated that statistical analysis of safety data in antimalarial drugs for malarial chemoprevention in pregnancy RCTs are inadequate. The analysis insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise antimalarial drug safety evidence development, based on the available data.

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“…If indeed these terms refer to different AEs, the differences should be clearly explained by the authors. This is especially an important next step for the incorporation of ICIs as part of standard cancer treatment modalities [33,34] since without the use of standardized terminologies and methods to consistently detect, collect, analyze and report irAEs [35,36], efforts to provide reliable estimations of irSAEs for each ICI medication and cancer type remain hindered.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Reporting of Safety and Immune-Related Adverse Events in Clinical Trials of FDA-Approved Immune Checkpoint Inhibitors in Oncology

Karimian¹,

Mavoungou²,

Salem³

et al. 2020

Preprint

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Background – While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. Methods – MEDLINE was searched via PubMed to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared reporting and evaluated concordance in reported safety data between both sources. Results – Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8% and 8.8% of published trials respectively, compared to 11.8% and 5.9% of registry results. Evaluating the concordance of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had concordant data between both sources.Conclusions – The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

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Analysis and reporting of adverse events in randomised controlled trials: a review

Cited by 149 publications

References 52 publications

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

Evaluation of the Reporting of Safety and Immune-Related Adverse Events in Clinical Trials of FDA-Approved Immune Checkpoint Inhibitors in Oncology

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