This document provides an overview of systematic reviews and meta-analyses, their application to medication safety data, and how to conduct such reviews. It defines systematic reviews and meta-analyses and explains how they are conducted more rigorously than traditional narratives. Reviews of safety data can help resolve inconsistencies across studies and increase precision through pooling of data. While less common than efficacy reviews, meta-analyses of both randomized trials and observational studies are valuable for understanding adverse events. It is important to search unpublished literature and include various study designs when reviewing safety. Quality assessment and reproducible search methods are also important aspects of conducting a rigorous systematic review or meta-analysis of medication safety data.

1. Systematic Review and Meta-Analysis
Applications in Medication Safety
Hadeel Alkofide
April 2017

2. Outline
• Overview on systematic reviews (SR) and meta-
analyses (MA)
• Application of SR/MA on safety data
• How to conduct a SR/MA on safety data?

3. Outline
• Overview on systematic reviews (SR) and meta-
analyses (MA)
• Application of SR/MA on safety data
• How to conduct a SR/MA on safety data?

4. “If only we knew what we know!”
“Anything you can do…………. I can do meta!”

5. What are Reviews?
Individual
studies
One review Why?
- Complex issue
- Small sample size in
individual studies
(increase precision)
- Resolve discrepancies
Narrative reviews
Systematic reviews (SR)
Meta-analyses (MA) of SR

6. How are SR and MA Conducted?
PICO
- Population
- Intervention
- Comparator
- Outcome
Define the question1
2 Search the literature
- MEDLINE,
EMBASE.. Etc.
- Grey literature
- Ask experts
- Hand search
3 Pull articles/Screen abstracts
- Apply inclusion/exclusion criteria
4 Read full paper
- Apply inclusion/exclusion criteria
5 Data abstraction
+ assess quality of included studies
6 Conduct analysis
i.e. perform Meta-
Analysis

7. How SR/MA Rank Compared to other Designs?
Systematic reviews and meta-
analyses (of RCTs)
Randomized controlled trials
(RCT’s)
Cohort studies
Case-control studies
Cross sectional studies
Case reports
King of the hill

8. What Questions can be Applied to SR/MA?
• Used to summarize evidence in behavioral, social and
health sciences
• In health sciences SR/MA can be conducted on:
Efficacy data
Safety data
Diagnostic tests
Risk factors for diseases (epidemiological data)
Economic evaluations

9. Outline
• Overview on systematic reviews (SR) and meta-
analyses (MA)
• Application of SR/MA on safety data
• How to conduct a SR/MA on safety data?

10. SR/MA on Adverse Events
• Not as common as
reviews on efficacy of
interventions
• One study showed that
only 5% of published SRs
were on adverse effects
• Although the number of
reviews ↑ over the years
Golder et al. Journal of Clinical Epidemiology. 2013

11. Why Less Reviews on Medication Safety?
• In clinical trials specifically, adverse events are poorly,
and inconsistently reported
• Difficulties in identifying relevant studies when using
standard systematic searches techniques
• Previously.. Lack of guidance on performing SR on
harm
New PRISMA checklist for safety data (2016)
Huang et al. Pharmacoepidemiology and Drug Safety. 2011
PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses

12. Using Pharmacoepidemiological Studies in
SR/MA of Safety Data
• Pharmacoepidemiological studies:
Observational studies
Individuals are exposed to drugs without a method
of assignment (non-interventional studies)
Play a major role when conducting SR/MA on
safety outcomes

13. Using Observational Studies vs RCTs
• A study compared the estimates of adverse events
derived from meta-analysis of RCTs vs. meta-analysis
of observational studies:
No difference in the pooled effect estimates of
adverse events between the two study designs
Golder et al. PLoS Medicine. 2011

14. Searching for Unpublished Studies
• Is it that important to search the grey literature?
Yes, especially when dealing with safety data

15. Adding Unpublished Reports
• Number of additional trials available for meta-analyses
when including unpublished reports
Golder et al. PLoS Medicine. 2016

16. Quality of Published SR/MA on Safety Data
• Comparison between the
years of 2008 and 2010-11
showed no difference on
quality of reporting over time
(P=0.079)
• Titles in fewer than half the
reviews
• Almost one third of reviews
did not clearly define the
adverse events reviewed
Zorzela et al. BMJ. 2014

17. Outline
• Overview on systematic reviews (SR) and meta-
analyses (MA)
• Application of SR/MA on safety data
• How to conduct a SR/MA on safety data?

18. SR/MA on Adverse Events… Example
Thomas et al. BMJ. 2015

19. SR/MA on Adverse Events… Example
Thomas et al. BMJ. 2015

20. Conducting a SR/MA on Safety Data
• Like any other review…. Mostly
• Look carefully for unpublished studies
• Include all study designs in your review when possible
• Assess quality of studies, similarly as you would for
efficacy data
• Have a clear and reproducible search strategy

21. Thank You
Questions