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European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

Chapter 10: Systematic reviews and meta-analysis

Identification and integration of evidence derived from results from several studies with the same or similar research objective can extend our understanding of the research question. A systematic literature review aims to collect in a systematic and explicit manner all empirical evidence that fits pre-specified eligibility criteria to answer a specific research question and to critically appraise relevant results. A meta-analysis involves the use of statistical techniques to integrate and summarise the results of identified studies. The focus of this activity may be to learn from the diversity of designs, results and associated gaps in knowledge as well as to obtain overall risk estimates. An example of a systematic review and meta-analysis of results of individual studies with potentially different designs is given in Variability in risk of gastrointestinal complications with individual NSAIDs: results of a collaborative meta-analysis (BMJ. 1996;312(7046):1563-6), which compared the relative risk of serious gastrointestinal complications reported with individual NSAIDs by conducting a systematic review of twelve hospital and community-based case-control and cohort studies and found a relation between use of the drugs and admission to hospital for haemorrhage or perforation.

Systematic review and meta-analysis of observational studies and other epidemiological sources are becoming as common as those of randomised clinical trials (RCTs). Challenges in systematic reviews that assess treatment harms (Ann Intern Med. 2005;142:1090-9) explains the different reasons why both are important in providing relevant information and knowledge for pharmacovigilance. However, the method of analysis differs when meta-analyses pool evidence from observational studies compared to RCTs. This also applies to network meta-analyses that are now being performed using observational studies (see NMA incorporating RWEOverview of evidence synthesis and network meta-analysis – RWE Navigator, and Chapter 16.1 of this Guide on comparative effectiveness research). It is also increasingly common to perform a meta-analysis of individual patient data which allows for additional opportunities but has challenges.

A detailed guidance on the methodological conduct and reporting of systematic reviews and meta-analysis is reported in Annex 1 of this Guide and includes links to several relevant resources.

It should be noted that meta-analyses, even of RCTs, shares characteristics with observational research as subjective criteria are often involved in the selection of studies to include. Careful planning in design of a meta-analysis and pre-specification of selection criteria, outcomes and analytical methods before review of any study results may thus contribute to the confidence placed in the results. A further useful reference is the CIOMS Working Group X Guideline on Evidence Synthesis and Meta-Analysis for Drug Safety (Geneva 2016).

Framework for the synthesis of non-randomised studies and randomised controlled trials: a guidance on conducting a systematic review and meta-analysis for healthcare decision making (BMJ Evid Based Med. 2020 Dec 9:bmjebm-2020-111493) provides guidance on when and how to combine evidence from observational studies and RCTs.

Renin-angiotensin-system inhibitors and all-cause mortality in patients with COVID-19: a systematic review and meta-analysis of observational studies (J Hypertens. 2021;39(4):784-794) included 31 cohort and three case-control studies which were combined and analysed separately due to the inherent differences in study designs. The meta-analysis Lopinavir/Ritonavir for COVID-19: a Systematic Review and Meta-Analysis(J Pharm Pharm Sci. 2021;24:246-57) compared the efficacy and safety of lopinavir/ritonavir to other treatment options using data up to April 2021 from 14 studies, including data from clinical registry databases. Safety of Tenofovir Disoproxil Fumarate (TDF) for Pregnant Women facing the COVID-19 Pandemic (Am J Epidemiol. 2021:kwab109) assessed the teratogenicity of tenofovir using a claims-based pregnancy cohort of women with HIV and combined the results with prior data by conducting a systematic literature review and a meta-analysis.