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Volume 178 - Issue 7

Determining the sample size in a clinical trial

Author:  Owen D Williamson

Med J Aust 2003; 178 (7): 358. || doi: 10.5694/j.1326-5377.2003.tb05240.x
Published online: 7 April 2003
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To the Editor: Evidence-based medicine should be supported by randomised controlled trials (RCTs) that show the efficacy of interventions in producing clinically relevant outcomes, not by those that show statistically significant, but clinically irrelevant, differences.

RCTs are designed to investigate whether an intervention in one homogeneous group results in a different outcome compared with no intervention, or a different intervention in an otherwise identical group.

Statistical analyses are performed to estimate the probability that any difference in outcome has arisen as the result of chance alone, and sample size is determined to control the probability of a real difference in outcome being overlooked by chance alone. However, statistical analyses provide no information about the clinical relevance of any difference in outcome. There is no validated method for determining a minimum clinically relevant difference in outcome (minimum important difference).

Kirby and colleagues suggest that, wherever possible, the minimum important difference in response should be determined from Phase II or pilot studies and expert opinion from colleagues.1 It is ironic that the clinical relevance of Level I evidence2 depends on determining the minimum important difference based on Level IV or Level V evidence.

Although the original CONSORT statement recommended describing the minimum important difference and indicating how the target sample size was projected,3 the most recent statement is less specific and only recommends describing how the sample size was determined.4 Neither statement requires investigators to specifically describe the method by which the minimum important difference was determined.

The minimum important difference must be justified so others can determine if the study has the power to detect a clinically relevant difference in outcome as the result of a particular intervention. Similarly, the minimum important difference must be stated so that any statistically significant difference in outcome can be judged for clinical relevance.

If the minimum important difference cannot be justified as being clinically relevant, the result of the study will be of statistical interest only, and valuable resources will have been wasted. While it is reasonable to suggest that sample size must be planned to ensure that research time, patient effort and support costs invested in any clinical trial are not wasted,5 manipulating the minimum important difference to allow an RCT to conform to these constraints cannot be justified unless the RCT can still detect a clinically relevant difference in outcome.

Author

  • Owen D Williamson

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