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. The search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. 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%). 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.

中文翻译：

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妊娠试验中疟疾化学预防安全性数据统计方法的系统评价

临床试验中的药物安全性评估提出了独特的分析挑战。其中一些包括调整个人随访时间、重复测量多个结果以及缺失数据等。此外，由于某些安全终点是意外的，因此预先指定适当的分析变得困难。尽管 CONSORT 等现有指南鼓励在临床试验中全面报告不良事件 (AE)，但它们为安全数据分析提供的详细信息有限。有限的指导方针可能会因未能考虑上述一些分析挑战而影响次优分析。存在此类挑战的一个典型例子是用于妊娠期间预防疟疾的抗疟药物试验。缺乏对抗疟药物安全性的适当标准化评估限制了得出安全性结论的能力。因此，进行了系统评价，以确定妊娠期预防性抗疟药物安全性统计分析的现行做法。检索包括五个数据库（PubMed、Embase、Scopus、Malaria in Pregnancy Library 和 Cochrane Central Register of Controlled Trials），以识别报道抗疟药物用于预防妊娠期疟疾的 III 期随机对照试验 (RCT) 的原始英文文章，这些试验发表于2010 年 1 月至 2019 年 7 月。本次综述纳入了 18 项试验，收集了包括 AE 在内的多项纵向安全结果。使用描述性统计对所有试验中的安全结果进行统计分析和报告；比例/计数 (n = 18, 100%) 和平均值/中位数 (n = 2, 11.1%)。结果呈现包括表格（n = 16，88.9%）和文字描述（n = 2，11.1%）。大多数试验报告了单变量推理方法（n = 16，88.9%）；包括卡方/Fisher 精确检验（n = 12，66.7%）、t 检验（n = 2，11.1%）和 Mann–Whitney/Wilcoxon 检验（n = 1，5.6%）。少数试验报告了多变量方法，包括泊松法和负二项式法（n = 3，16.7%）。任何报告疗效缺失数据的试验均未报告对缺失疗效数据与安全性结果之间潜在联系的评估（n = 7，38.9%）。审查表明，妊娠期随机对照试验中抗疟疾药物用于疟疾化学预防的安全性数据的统计分析是不够的。这些分析没有充分考虑多种安全结果，包括潜在依赖性、随访时间和信息缺失数据，这些可能会影响基于现有数据的抗疟药物安全证据的开发。