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Published on: September 20, 2019
Changes to aspects of ongoing randomised controlled trials with fixed designs
Xanthi Coskinas1, John Simes1, Manjula Schou2,3
1The National Health and Medical Research Council Clinical Trial Centre, University of Sydney, Camperdown, NSW, 2050, Australia.
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.
Insights
Modifying clinical trial designs requires care. Legitimate changes, made without knowledge of treatment allocation, maintain unbiased results. Illegitimate changes, however, introduce significant bias and inflate error rates in randomised clinical trials.
Area of Science:
- Clinical Trials Methodology
- Biostatistics
- Evidence-Based Medicine
Background:
- Randomised clinical trials (RCTs) may require design modifications despite initial planning.
- Distinguishing between legitimate and illegitimate changes is crucial for trial integrity.
Purpose of the Study:
- To differentiate legitimate from illegitimate changes in ongoing RCTs.
- To provide guidance for clinical trialists and stakeholders on managing trial modifications.
Main Methods:
- Simulated trial datasets were generated under null (H0) and alternative (H1) hypotheses.
- Assessed strategies of design/analysis changes with (illegitimate) versus without (legitimate) knowledge of treatment allocation.
- Evaluated performance using Type 1 error rates and treatment effect bias.
Main Results:
- Illegitimate changes caused 61% relative bias (H1) and 23% Type 1 error rate (H0).
- Legitimate changes yielded unbiased estimates (H1) without inflating Type 1 error (H0).
Conclusions:
- Modifications to RCT design/analysis may be necessary due to unforeseen circumstances.
- Changes made with knowledge of treatment allocation risk introducing bias.
- Legitimate changes must be documented to ensure validity and stakeholder confidence.
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