Editorial

Meta-analysis in clinical research

Steven A Julious

Statistical Methods in Medical Research

22(2) 115116
! The Author(s) 2013
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DOI: 10.1177/0962280213482391
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Meta-analysis is important in the evaluation of therapies1,2 for integrating the results of individual
studies in order to advance or inform clinical research. In this special issue, dierent aspects of metaanalysis are reviewed using case studies to illustrate the methodologies being described.
There can be issues when evaluating evidence when the events being observed are rare.3 Lane
compares available methods for binary data considering dierent summary measures such as riskdierence, relative-risk and odds-ratio scale as well as xed and random-eect methods in the
assessment. The paper also highlights the benet of how graphical approaches can add value.4
A case study is presented by Julious to highlight issues in evaluating evidence for safety and
ecacy, which updates previous analyses with additionally reported trials.5 These data also consider
the problem of the event of interest being rare. Graphical approaches are highlighted to investigate
the assumptions in a meta-analysis.6
Often, however, a direct comparison of two therapies is not possible and indirect
comparisons need to be made through a network meta-analysis.7 A sparsely connected network
of 10 treatments for the treatment of diabetes is used by Senn et al. to make points about approaches
to analysis.8 Graphical approaches, both of the network and of the results, are again described to
summarise the data.
Indirect comparisons are also used in the assessment, and design, of non-inferiority studies.9,10
In non-inferiority clinical trials, a test treatment is compared to an active-control rather than
to placebo when randomising to placebo is unethical or not feasible. A critical question is
whether the test treatment would have been superior to placebo, had placebo been used in the
non-inferiority trial.11,12 This question, as highlighted by Schmidli et al.,13 can only be addressed
indirectly, based on information from relevant historical trials with data on active-control and
placebo.
As highlighted multivariate meta-analysis is becoming increasingly popular. The advantages and
limitations of multivariate meta-analysis have been discussed.14 The main limitation being
computational complexity and hence, in a timely paper, Mavridis and Salanti15 review the
statistical methods and the related software for multivariate meta-analysis.
Pooling evidence from individual trials is important in the evaluation of research. For the
individual trials adaptive designs have been recommended.16,17 However, there can be issues in
pooling evidence when trials have stopped early.18,19 Bassler et al.20 review controversies
associated with randomised controlled trials stopped early for apparent benet and discussed how
pooled eects from meta-analyses including trials stopped early could potentially overestimate
an eect.
University of Sheffield, UK
Corresponding author:
Steven A Julious, Medical Statistics Group, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK.
Email: S.A.Julious@Sheffield.ac.uk

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Statistical Methods in Medical Research 22(2)

In summary, this special issue covers many practical issues with meta-analysis. There is a strong
emphasis on graphical approaches to assist in interpretation. There have been many advances in
recent years in meta-analysis such as indirect approaches via networks and these are discussed
in detail.
References
1. Whitehead A. Meta-analysis of controlled clinical trials,
Chichester: Wiley.
2. Senn SJ. Statistical issues in drug development, 2nd ed.
Hoboken: Wiley, 2007.
3. Lane PW. Meta-analysis of incidence of rare events. Stat
Meth Med Res 2013; 22(2): 117132.
4. Amit O, Heiberger R and Lane PW. Graphical approaches
to the analysis of safety data from clinical trials.
Pharmaceut Stat 2008; 7: 2035.
5. Julious SA. Efficacy and suicidal risk for antidepressants
in paediatric and adolescent patients. Stat Meth Med Res
2013; 22(2): 190218.
6. Julious SA and Whitehead A. Investigating the assumption
of homogeneity of treatment effects in clinical studies with
application to meta-analysis. Pharmaceut Stat 2012; 11(1):
4956.
7. Salanti G, Higgins JP, Ades AE, et al. Evaluation of
networks of randomized trials. Stat Meth Med Res 2008;
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8. Senn S, Gavini F, Magrez D, et al. Issues in performing a
network meta-analysis. Stat Meth Med Res 2013; 22(2):
169189.
9. Julious SA and Wang SJ. Issues with indirect comparisons
in clinical trials particularly with respect to non-inferiority
trials. Drug Inform J 2008; 42(6): 625633.
10. Julious SA. The ABC of non-inferiority margin setting
from indirect comparisons. Pharmaceut Stat 2011; 10(5):
448453.
11. Witte S, Schmidli H, OHagan A, et al. Designing a noninferiority study in kidney transplantation: a case study.
Pharmaceut Stat 2011; 10: 427432.

12. Julious SA and Owen RJ. A comparison of methods for

sample size estimation for non-inferiority studies with
binary outcomes. Stat Meth Med Res 2011; 20(6): 595612.
13. Schmidli H, Wandel S and Neuenschwander B. The
network meta-analytic-predictive approach to noninferiority trials. Stat Meth Med Res 2013; 22(2): 219240.
14. Ishak KJ, Platt RW, Joseph L, et al. Impact of
approximating or ignoring within-study covariances in
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multivariate meta-analysis. Stat Meth Med Res 2013;
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18. Bassler D, Briel M, Montori VM, et al. Stopping
randomized trials early for benefit and estimation of
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19. Mueller PS, Montori VM, Bassler D, et al. Ethical issues in
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20. Bassler D, Montori VM, Briel M, et al. Reflections on
meta-analyses involving trials stopped early for benefit: is
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