PMID- 22796636
OWN - NLM
STAT- MEDLINE
DCOM- 20130318
LR  - 20220129
IS  - 1740-7753 (Electronic)
IS  - 1740-7745 (Linking)
VI  - 9
IP  - 5
DP  - 2012 Oct
TI  - When inferiority meets non-inferiority: implications for interim analyses.
PG  - 605-9
LID - 10.1177/1740774512453220 [doi]
AB  - 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, Delta, 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 Delta, 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.
FAU - Bratton, Daniel J
AU  - Bratton DJ
AD  - MRC Clinical Trials Unit, London, UK. daniel.bratton@ctu.mrc.ac.uk
FAU - Williams, Hywel C
AU  - Williams HC
FAU - Kahan, Brennan C
AU  - Kahan BC
FAU - Phillips, Patrick P J
AU  - Phillips PP
FAU - Nunn, Andrew J
AU  - Nunn AJ
LA  - eng
GR  - 06/403/51/DH_/Department of Health/United Kingdom
GR  - HTA/06/403/51/DH_/Department of Health/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120713
PL  - England
TA  - Clin Trials
JT  - Clinical trials (London, England)
JID - 101197451
RN  - 0 (Adrenal Cortex Hormones)
RN  - 0 (Anti-Bacterial Agents)
RN  - 9PHQ9Y1OLM (Prednisolone)
RN  - N12000U13O (Doxycycline)
SB  - IM
MH  - Adrenal Cortex Hormones/therapeutic use
MH  - Anti-Bacterial Agents/therapeutic use
MH  - Computer Simulation
MH  - Doxycycline/therapeutic use
MH  - Humans
MH  - *Models, Statistical
MH  - Pemphigoid, Bullous/drug therapy
MH  - Prednisolone/therapeutic use
MH  - Probability
MH  - Randomized Controlled Trials as Topic/*methods
MH  - *Research Design
MH  - Sample Size
EDAT- 2012/07/17 06:00
MHDA- 2013/03/19 06:00
CRDT- 2012/07/17 06:00
PHST- 2012/07/17 06:00 [entrez]
PHST- 2012/07/17 06:00 [pubmed]
PHST- 2013/03/19 06:00 [medline]
AID - 1740774512453220 [pii]
AID - 10.1177/1740774512453220 [doi]
PST - ppublish
SO  - Clin Trials. 2012 Oct;9(5):605-9. doi: 10.1177/1740774512453220. Epub 2012 Jul 
      13.