Defining the question

Any systematic review should pose sensible questions that are clinically meaningful and methodologically appropriate. Although meta-analyses often emphasize the large numbers of individuals that are included, it is important that these numbers are not achieved at the expense of combining trials inappropriately. There is always likely to be a degree of trade-off between achieving statistical power and addressing tightly defined questions.

It will rarely be possible to combine trials comparing exactly the same interventions, and it is inevitable and appropriate to accept some variation, for example, in doses or scheduling of drugs or in the composition of regimens within a class of drugs. Indeed, it can be argued that a certain amount of clinical heterogeneity between trials is a good thing, because it is likely to be more representative of the real world. However, it is not usually sensible to combine very different interventions. Although there is inevitably some subjectivity in defining the scope of a systematic review, the comparisons should be driven by the clinical question to be addressed. Put simply, the systematic review should be specified in such a way that results will be clinically meaningful. For example, if a review of the role of palliative therapy in advanced lung cancer compared any palliative therapy including chemotherapy, radiotherapy, or nutritional support versus no treatment, it would include large numbers of patients. However, the results would be likely to be difficult to interpret. If good evidence of an effect was shown by the meta-analysis, it would not be clear which therapy or therapies were responsible for the effect and whether all or a subset of interventions should be recommended. If it showed no effect, the metaanalysis could be rightly criticized on the grounds that the results of trials of effective types of therapy may have been swamped by trials of ineffective therapies. So although numbers would be much reduced it would probably be better to look independently at each individual palliative therapy.

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