PMID- 32197619 OWN - NLM STAT- MEDLINE DCOM- 20201105 LR - 20230725 IS - 1475-2875 (Electronic) IS - 1475-2875 (Linking) VI - 19 IP - 1 DP - 2020 Mar 20 TI - Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials. PG - 119 LID - 10.1186/s12936-020-03190-z [doi] LID - 119 AB - 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. METHODS: 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. 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. FAU - Patson, Noel AU - Patson N AD - School of Public Health, University of the Witwatersrand, Johannesburg, South Africa. AD - University of Malawi, College of Medicine, Blantyre, Malawi. FAU - Mukaka, Mavuto AU - Mukaka M AD - Mahidol Oxford Tropical Medicine Research Unit (MORU), Bangkok, Thailand. AD - Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. FAU - Otwombe, Kennedy N AU - Otwombe KN AD - School of Public Health, University of the Witwatersrand, Johannesburg, South Africa. AD - Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. FAU - Kazembe, Lawrence AU - Kazembe L AD - Department of Biostatistics, University of Namibia, Windhoek, Namibia. FAU - Mathanga, Don P AU - Mathanga DP AD - University of Malawi, College of Medicine, Blantyre, Malawi. FAU - Mwapasa, Victor AU - Mwapasa V AD - University of Malawi, College of Medicine, Blantyre, Malawi. FAU - Kabaghe, Alinune N AU - Kabaghe AN AD - University of Malawi, College of Medicine, Blantyre, Malawi. FAU - Eijkemans, Marinus J C AU - Eijkemans MJC AD - Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. FAU - Laufer, Miriam K AU - Laufer MK AUID- ORCID: 0000-0001-8300-9593 AD - Center for Vaccine Development and Global Health, University of Maryland, School of Medicine, 685 W. Baltimore St., HSF-1 Room 480, Baltimore, MD, 21201, USA. mlaufer@som.umaryland.edu. FAU - Chirwa, Tobias AU - Chirwa T AD - School of Public Health, University of the Witwatersrand, Johannesburg, South Africa. LA - eng GR - D43 TW010075/TW/FIC NIH HHS/United States GR - D43TW010075/TW/FIC NIH HHS/United States PT - Journal Article PT - Systematic Review DEP - 20200320 PL - England TA - Malar J JT - Malaria journal JID - 101139802 RN - 0 (Antimalarials) SB - IM MH - Adult MH - Antimalarials/*administration & dosage/adverse effects MH - Chemoprevention/methods/*statistics & numerical data MH - Data Interpretation, Statistical MH - Female MH - Humans MH - Malaria/*prevention & control MH - Pregnancy MH - Pregnancy Complications, Infectious/parasitology/*prevention & control MH - Randomized Controlled Trials as Topic PMC - PMC7085184 OTO - NOTNLM OT - Clinical trials OT - Malaria OT - Pregnancy OT - Prevention OT - Safety OT - Statistical methods COIS- The authors declare that they have no competing interests. EDAT- 2020/03/22 06:00 MHDA- 2020/11/06 06:00 PMCR- 2020/03/20 CRDT- 2020/03/22 06:00 PHST- 2019/12/14 00:00 [received] PHST- 2020/03/12 00:00 [accepted] PHST- 2020/03/22 06:00 [entrez] PHST- 2020/03/22 06:00 [pubmed] PHST- 2020/11/06 06:00 [medline] PHST- 2020/03/20 00:00 [pmc-release] AID - 10.1186/s12936-020-03190-z [pii] AID - 3190 [pii] AID - 10.1186/s12936-020-03190-z [doi] PST - epublish SO - Malar J. 2020 Mar 20;19(1):119. doi: 10.1186/s12936-020-03190-z.