PubMed · 11778590
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D Parry. 2001-12-15. Monitoring clinical trials. Several points are contentious.. https://pubmed.ncbi.nlm.nih.gov/11778590/
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When designing a clinical trial to compare the effect of different treatments on response, a key issue facing the statistician is to determine how large a study is necessary to detect a clinically important difference with sufficient power. This is the case whether the study will be analysed only once (single-analysis) or whether it will be monitored periodically with the possibility of early stopping (group-sequential). Standard sample size calculations are based on both the magnitude of difference that is considered clinically important as well as values for the nuisance parameters in the statistical model. For planning purposes, best guesses are made for the value of the nuisance parameters and these are used to determine the sample size. However, if these guesses are incorrect this will affect the subsequent power to detect the clinically important difference. It is argued in this paper that statistical precision is directly related to Statistical Information and that the study should continue until the requisite statistical information is obtained. This is referred to as information-based design and analysis of clinical trials. We also argue that this type of methodology is best suited with group-sequential trials which monitor the data periodically and allow for estimation of the statistical information as the study progresses.
In the standard approach to designing definitive clinical trials, the primary endpoint and test statistic to be used for the primary analysis are specified before trial initiation. The false positive error rate for the null hypothesis and statistical power to detect the targeted size of treatment effect are also specified. Standard monitoring procedures, such as the group sequential guidelines, enable interim monitoring while maintaining the integrity of this approach. In contrast, adaptive monitoring procedures seek to provide flexibility to modify these pre-specified design features during the course of the trial. However, these procedures have several undesirable properties, including lesser statistical efficiency, reduced interpretability of primary outcome results, basing design changes on unreliable interim estimates of efficacy, risks to the integrity and credibility of the trial, loss of flexibility to use emerging results from external sources to alter key design features, and overemphasis of the importance of statistical significance relative to clinical significance.
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