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

Abstract

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.

Statistical methods for the analysis of adverse event data in randomised controlled trials: a scoping review and taxonomy

“…For example, harm outcomes are often accompanied with additional information such as the number of occurrences, severity, timing and duration that need to be taken into consideration. However, the predominant practice is to reduce this information to simple binary counts [4,19,[70][71][72]. We believe these challenges do not justify the prevalent use of simplistic analysis approaches for AE analysis.…”

Understanding current practice, identifying barriers and exploring priorities for adverse event analysis in randomised controlled trials: an online, cross-sectional survey of statisticians from academia and industry

“…1 2 4 14 15 It has also been argued that such guidelines do not go far enough and fail to account for the complex nature of harm outcomes data. 5 Tutorial papers or case studies detailing examples of appropriate analysis could lead to wider adoption of such recommendations and to improvements in analysis practices, and development of such resources was highlighted as a priority by workshop participants. While the acquirement of the necessary knowledge and skills to implement new methods is essential, so too is increasing awareness of good practices and alternative methods.…”

“…Open access data are not being analysed to its full potential. [1][2][3][4][5] Most notable inadequacies include ignoring information on repeated events and dichotomising continuous clinical and laboratory outcomes, with binary counts often presented using simple tabulations, indicating whether an event did or did not occur. Little formal analysis is performed but a comprehensive methods review undertaken by the authors revealed that there have been many published statistical methods proposed specifically to analyse adverse event data for both the interim and the final analysis.…”

Statistical methods for the analysis of adverse event data in randomised controlled trials: a scoping review and taxonomy

“…However, the predominant practice is to reduce this information to simple binary counts. [4,19,[70][71][72] We believe these challenges do not justify the prevalent use of simplistic analysis approaches for AE analysis.…”