Published in:
Open Access 01-12-2020 | Coronary Heart Disease | Methodology
Changes to aspects of ongoing randomised controlled trials with fixed designs
Published in: Trials | Issue 1/2020
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Background
Despite careful planning, changes to some aspects of an ongoing randomised clinical trial (RCT), with a fixed design, may be warranted. We sought to elucidate the distinction between legitimate versus illegitimate changes to serve as a guide for less experienced clinical trialists and other stakeholders.
Methods
Using data from a large trial of statin therapy for secondary prevention, we generated a set of simulated trial datasets under the null hypothesis (H0) and a set under an alternative hypothesis (H1). Through analysis of these simulated trials, we assessed the performance of the strategy of changing aspects of the design/analysis with knowledge of treatment allocation (illegitimate) versus the strategy of making changes without knowledge of treatment allocation (legitimate). Performance was assessed using the type 1 error, as well as measures of absolute and relative bias in the treatment effect.
Results
Illegitimate changes led to a relative bias of 61% under H1, and a type 1 error rate under H0 of 23%—well in excess of the 5% significance level targeted. Legitimate changes produced unbiased estimates under H1 and did not inflate the type 1 error rate under H0.
Conclusions
Changes to pre-specified aspects of the design and analysis of an ongoing RCT may be a necessary response to unforeseen circumstances. Such changes risk introducing a bias if undertaken with knowledge of treatment allocation. Legitimate changes need to be adequately documented to provide assurance to all stakeholders of their validity.