Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK.
Malar J. 2023 Feb 10;22(1):50. doi: 10.1186/s12936-023-04441-5.
For the results of clinical trials to have external validity, the patients included in the study must be representative of the population presenting in the general clinical settings. A scoping literature review was performed to evaluate how the eligibility criteria used in anti-malarial efficacy and safety trials translate into patient selection.
A search of the WorldWide Antimalarial Resistance Network (WWARN) Clinical Trials Publication Library, MEDLINE, The Cochrane Library, and clinicaltrials.gov was conducted to identify trials investigating anti-malarial efficacy and safety, published between 14th April 2001 and 31st December 2017. An updated search using the WWARN Clinical Trial Publication Library was undertaken to identify eligible publications from 1st January 2018 to 31st July 2021. The review included studies in patients of any age with uncomplicated malaria and any pharmaceutical therapeutic intervention administered. The proportion of trials with malaria-positive patients excluded was calculated and linked to the reported reason for exclusion. A subgroup analysis on eligibility criteria and trial baseline demographics was conducted to assess whether criteria are complied with when recruiting patients.
Out of 847 studies, 176 (21%) trials were included in the final synthesis, screening a total of 157,516 malaria-positive patients, of whom 56,293 (36%) were enrolled and treated. Across the 176 studies included, 84 different inclusion and exclusion criteria were identified. The reason for exclusion of patients who tested positive for malaria was reported in 144 (82%) studies. Three criteria account for about 70% of malaria-positive patients excluded: mixed-species malaria infections or other specific Plasmodium species, parasite counts outside the set study ranges, and refusal of consent.
Nearly two-thirds of the malaria-positive subjects who present to health facilities are systematically excluded from anti-malarial treatment trials. Reasons for exclusions are largely under-reported. Anti-malarial treatment in the general population is informed by studies on a narrow selection of patients who do not fully represent the totality of those seeking antimalarial treatment in routine practice. While entry criteria ensure consistency across trials, pragmatic trials are also necessary to supplement the information currently available and improve the external validity of the findings of malaria clinical trials.
为使临床试验结果具有外部有效性，研究中纳入的患者必须能够代表一般临床环境中出现的人群。进行了范围广泛的文献综述，以评估抗疟疗效和安全性试验中使用的纳入标准如何转化为患者选择。
对世界疟疾研究网络（WWARN）临床试验出版文库、MEDLINE、Cochrane 图书馆和 clinicaltrials.gov 进行了搜索，以确定在 2001 年 4 月 14 日至 2017 年 12 月 31 日期间发表的调查抗疟疗效和安全性的试验。使用 WWARN 临床试验出版文库进行了最新搜索，以确定 2018 年 1 月 1 日至 2021 年 7 月 31 日期间符合条件的出版物。该综述纳入了任何年龄患有无并发症疟疾和任何药物治疗干预的患者的研究。计算了疟疾阳性患者被排除的试验比例，并将其与报告的排除原因联系起来。进行了纳入标准和试验基线人口统计学的亚组分析，以评估招募患者时是否符合标准。
在 847 项研究中，有 176 项（21%）试验最终被纳入综合分析，共筛查了 157516 例疟疾阳性患者，其中 56293 例（36%）被纳入并接受治疗。在纳入的 176 项研究中，共确定了 84 种不同的纳入和排除标准。在 144 项（82%）研究中报告了疟疾阳性患者被排除的原因。有三个标准占被排除的疟疾阳性患者的 70%左右：混合种疟疾感染或其他特定的疟原虫种、寄生虫计数超出设定的研究范围以及拒绝同意。
近三分之二的到医疗机构就诊的疟疾阳性患者被系统地排除在抗疟治疗试验之外。排除的原因在很大程度上没有得到充分报告。一般人群中的抗疟治疗是基于对不符合实际寻求抗疟治疗的患者的窄选择患者进行的研究。虽然纳入标准确保了试验之间的一致性，但也需要进行实用试验来补充现有信息，并提高疟疾临床试验结果的外部有效性。
