Abstract | BACKGROUND: The objective of a non-inferiority trial is to determine whether a new or existing treatment is not less effective than another existing or current treatment by more than a pre-specified margin, Δ, usually with the requirement that the new treatment has some other advantage such as reduced cost or lower toxicity. A possible but unusual result in a non-inferiority trial is for the confidence interval for the treatment effect to lie between zero and Δ, implying that the new treatment is both inferior and non-inferior to the control. Such a result could occur in non-inferiority trials with large sample sizes or large non-inferiority margins. The possibility of this scenario occurring has implications for interim analyses. In standard superiority trials, stopping guidelines are often based on the p value obtained from testing whether treatments are equally effective. In non-inferiority trials, however, even if a new treatment is found to be inferior to the control at an interim analysis, there may still be a reasonable chance of demonstrating non-inferiority in the final analysis. PURPOSE: To explore the issues arising from trials where a simultaneously inferior and non-inferior result could occur and to describe appropriate methods for deciding whether such trials should be stopped for futility at an interim analysis. METHODS: Conditional power is used to assess futility or the inability of the trial to show non-inferiority at the final analysis, by calculating the probability of demonstrating non-inferiority in the final analysis conditional on the observed results and upon assumptions on the future results of the trial. The Bullous Pemphigoid Steroids and Tetracyclines Study ( BLISTER) trial is an example of a trial where a simultaneous inferior and non-inferior result could occur. A method for calculating conditional power for non-inferiority using simulations is described and applied at a hypothetical interim analysis of this trial. RESULTS: Stopping guidelines for futility based on conditional power are shown to be better suited to non-inferiority trials than the typical methods used in superiority trials. Simulations are a straightforward and flexible way of calculating conditional power. LIMITATIONS: Calculating conditional power relies on assumptions about future treatment efficacy, and therefore, a number of different conditional power values can be obtained. Careful consideration should be given to which assumptions are most likely to be true. Additionally, when choosing a stopping guideline for futility, consideration needs to be given to avoid overinflating the type II error rate. CONCLUSIONS: Conditional power is an appropriate tool for defining stopping guidelines for futility in non-inferiority trials, particularly those with large non-inferiority margins.
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Authors | Daniel J Bratton, Hywel C Williams, Brennan C Kahan, Patrick P J Phillips, Andrew J Nunn |
Journal | Clinical trials (London, England)
(Clin Trials)
Vol. 9
Issue 5
Pg. 605-9
(Oct 2012)
ISSN: 1740-7753 [Electronic] England |
PMID | 22796636
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adrenal Cortex Hormones
- Anti-Bacterial Agents
- Prednisolone
- Doxycycline
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Topics |
- Adrenal Cortex Hormones
(therapeutic use)
- Anti-Bacterial Agents
(therapeutic use)
- Computer Simulation
- Doxycycline
(therapeutic use)
- Humans
- Models, Statistical
- Pemphigoid, Bullous
(drug therapy)
- Prednisolone
(therapeutic use)
- Probability
- Randomized Controlled Trials as Topic
(methods)
- Research Design
- Sample Size
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